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Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics
Abstract
The emerging therapeutic efficacy of ketamine and classical psychedelics for depression has inspired tremendous interest in the underlying neurobiological mechanisms. We review preclinical and clinical evidence supporting neuroplasticity as a convergent downstream mechanism of action for these novel fast-acting antidepressants. Through their primary glutamate or serotonin receptor targets, ketamine and psychedelics [psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT)] induce synaptic, structural, and functional changes, particularly in pyramidal neurons in the prefrontal cortex. These include increased glutamate release, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activation, brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR)-mediated signaling, expression of synaptic proteins, and synaptogenesis. Such influences may facilitate adaptive rewiring of pathological neurocircuitry, thus providing a neuroplasticity-focused framework to explain the robust and sustained therapeutic effects of these compounds.
... MDMA, psychedelics, and ketamine have plausible therapeutic mechanisms related to increasing neuro-metaplasticity in the brain via neurotrophic signaling mediated by increased BDNF secondary to 5-HT2A signaling (Aleksandrova & Phillips, 2021;de Vos, Mason, & Kuypers, 2021;Holas & Kami nska, 2023). Additionally, the activation of mammalian target of rapamycin (mTOR) may also be involved, specifically by classic psychedelics and ketamine (Aleksandrova & Phillips, 2021;Holas & Kami nska, 2023;Inserra, De Gregorio, & Gobbi, 2021;Ly et al., 2018). ...
... MDMA, psychedelics, and ketamine have plausible therapeutic mechanisms related to increasing neuro-metaplasticity in the brain via neurotrophic signaling mediated by increased BDNF secondary to 5-HT2A signaling (Aleksandrova & Phillips, 2021;de Vos, Mason, & Kuypers, 2021;Holas & Kami nska, 2023). Additionally, the activation of mammalian target of rapamycin (mTOR) may also be involved, specifically by classic psychedelics and ketamine (Aleksandrova & Phillips, 2021;Holas & Kami nska, 2023;Inserra, De Gregorio, & Gobbi, 2021;Ly et al., 2018). At least part of MDMA's structural plasticity is related to 5-HT2A receptor activation, as the administration of ketanserin, a 5-HT2A receptor antagonist, blocked the effects of neuritogenesis and spinogenesis (Ly et al., 2018). ...
... Neuroplasticity is suggested to play a significant role in the therapeutic effects of psychedelics, MDMA, and meditation, ultimately promoting lasting changes in brain structure and function (Aleksandrova & Phillips, 2021;de Vos et al., 2021;Felsch & Kuypers, 2022;Inserra et al., 2021;Kral et al., 2019;Ly et al., 2018;Moliner et al., 2023;Vargas et al., 2023). As previously discussed, psychedelics and MDMA may promote BDNF-mediated neuroplasticity, resulting in the growth of dendrites and synapse formation, which has been suggested to enhance cognitive flexibility, emotional resilience, memory reconsolidation, and psychological well-being. ...
Background and aims
Psychedelic and MDMA-assisted psychotherapy are at the forefront of new treatment models for mental illnesses such as PTSD and depression, as well as improving well-being. Mindfulness meditation and loving-kindness meditation have also gained research traction, showing promise for enhancing emotional regulation and psychological well-being. This paper explores the therapeutic convergence of these modalities, highlighting their neurobiological, psychological, and phenomenological overlap, and suggesting potential bidirectional synergy as a foundation for psychedelic or MDMA-assisted therapy.
Methods
A narrative and theoretical review of the current literature was conducted, examining the neurobiological, psychological, and phenomenological effects of MDMA, psychedelics, and meditation. Studies focusing on their potential synergy and mechanisms of action were prioritized and used as a backing for a theoretical framework.
Results
Psychedelics may improve psychological flexibility, prosocial behaviors, empathy, and neuroplasticity. Meditation research suggests similar benefits, including enhanced decentering capacity, emotional regulation, and well-being. Both modalities influence overlapping neural circuitry, particularly the amygdala, hippocampus, and default mode network. Integrating meditation with MDMA or psychedelic-assisted therapy may stabilize insights gained during altered states of consciousness, promote sustained therapeutic benefits, and minimize distress during therapy.
Conclusions
The convergence of meditation and psychedelics or MDMA-assisted therapy is a novel and promising approach for enhancing mental health treatments. Future research should investigate structured protocols combining these modalities, focusing on optimizing “set and setting” and long-term integration practices.
... Accordingly, impaired or maladaptive neuroplasticity has been linked to several neurological and neuropsychiatric disorders, such as depression and age-related cognitive decline [5]. Psychedelics might mitigate synaptic deficit, neuronal degeneration, and the loss of network connectivity, which are all linked to chronic stress, sustained neuroinflammation, depression, and treatment resistance [6]. This potential for neuroplasticity and recovery is one of the reasons underlying the exploration of psychedelics as new treatments for mental and cognitive disorders. ...
... The activation of this pathway also initiates a cascade of neurobiological events eventually leading, among others, to an increased expression of BNDF. In particular, DMT has been associated with an increase in peripheral BDNF levels, highlighting a clear impact of psychedelics on this important neurotrophic factor [6,14]. Variability in individual responses; potential for adverse psychological effects. ...
... Notably, these substances are able to induce long-lasting alterations in synaptic function and morphology also at the level of pyramidal neurons. As such, psychedelics have been linked to a temporary rise in cortical glutamate release and prolonged activation of excitatory neurotransmission in pyramidal neurons, primarily within the PFC [6], thus suggesting a role also at premotor and motor level. ...
... inhibitory interneurons (Zanos and Gould, 2018), leading to a paradoxical increase in glutamate release in the brain (Moghaddam et al., 1997). Glutamate activates postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, resulting in increased excitability of neurons (Aleksandrova and Phillips, 2021;Aleksandrova et al., 2017). In turn, AMPA receptor activation potentiates the release of brain-derived neurotrophic factor (BDNF), which upon binding to tyrosine receptor kinase B (TrkB) potentiates the downstream mammalian/mechanistic target of rapamycin (mTOR) pathway to influence synaptic protein synthesis (Aleksandrova and Phillips, 2021;Aleksandrova et al., 2017;Glavonic et al., 2024). ...
... Glutamate activates postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, resulting in increased excitability of neurons (Aleksandrova and Phillips, 2021;Aleksandrova et al., 2017). In turn, AMPA receptor activation potentiates the release of brain-derived neurotrophic factor (BDNF), which upon binding to tyrosine receptor kinase B (TrkB) potentiates the downstream mammalian/mechanistic target of rapamycin (mTOR) pathway to influence synaptic protein synthesis (Aleksandrova and Phillips, 2021;Aleksandrova et al., 2017;Glavonic et al., 2024). Ketamine also potentiates the trafficking of AMPA receptors to the postsynaptic membrane (Aleksandrova et al., 2017;Glavonic et al., 2024), which is critical for long-term potentiation (LTP) and the strengthening of synapses underlying learning and memory (Diaz-Alonso and Nicoll, 2021). ...
Introduction
Ketamine, a multimodal dissociative anesthetic, is widely used as a trauma analgesic in emergency situations. Ketamine is also used to treat psychiatric disorders due to its broad application potential, including treatment-resistant major depression. However, its impacts on the development of post-traumatic stress disorder (PTSD) and its potential as a treatment for PTSD are controversial. PTSD is marked by persistent and intrusive memories of traumatic event(s) and re-experiencing of the traumatic memories when exposed to trauma-related stimuli. Individuals with PTSD are often treated with prolonged exposure therapy (PE), in which they are gradually exposed to stimuli that remind them of the previous traumatic memory. If successful, they may learn that the previously traumatic stimuli are no longer threatening, a process known as fear extinction. Although fear extinction can be studied in laboratory animals, previous preclinical literature on the effects of ketamine on fear extinction has been inconsistent.
Methods
Thus, we summarized the existing preclinical literature examining effects of ketamine on fear extinction and its potential molecular mechanisms.
Results
Studies found that ketamine may enhance, impair, have no effect, or have mixed effects on fear extinction. These discrepancies may be attributed to differences in dosage, route, and timing of ketamine administration.
Discussion
We conclude the review with recommendations for future research on ketamine and PTSD such as the inclusion of more female subjects, clinically relevant doses and routes of ketamine administration, and more comprehensive behavioral assays that are relevant to PTSD in humans to enhance translation between preclinical and clinical research.
... effects suggest that neuroplasticity may serve as the unifying core mechanism underlying their therapeutic action (22). While much attention has focused on their profound and often ineffable psychoactive phenomenology, psychedelics' neurobiological mechanisms are equally germane. ...
... At the molecular level, psychoplastogens engage key signaling pathways that drive synaptic growth and neural reorganization (23). For example, ketamine acts through the NMDA receptor, leading to a surge in glutamate release, AMPA receptor activation, and subsequent stimulation of pathways such as brain-derived neurotrophic factor (BDNF) and mTOR, which support synaptogenesis and dendritic growth (22,(39)(40)(41). Similarly, MDMA modulates monoamine pathways, enhancing BDNF expression and synaptic plasticity (42,43). ...
... Functional magnetic resonance imaging (fMRI) and electrophysiological tools such as magnetoencephalography (MEG) are notable developments that were unavailable to researchers during the first surge in psychedelic research in the early twentieth century. Images of the "brain on LSD" from the seminal study by Carhart-Harris, Muthukumaraswamy, et al. (2016), as well as the now-famous image of brain functional networks on psilocybin versus placebo from Petri et al. (2014), sparked a renewed interest in psychedelics amongst both academic and public audiences, and were central to the development of the neuroplasticity hypothesis, which posits that the subjective and therapeutic effects of psychedelics are driven by underlying changes in neuroplasticity (Sumner & Lukasiewicz, 2023;de Vos et al., 2021;Aleksandrova & Phillips, 2021;. Neuroimaging will likely continue to be a cornerstone of research into the neural correlates of psychedelic experiences over the next decade. ...
... A driving narrative in psychedelic neuroscience at present is that post-acute changes are, in part, driven by enhanced neuroplasticity post-dose (Aleksandrova and Phillips, 2021;Nutt et al., 2023), as evidenced by preclinical in vitro and in vivo animal work (Calder and Hasler, 2023;Vargas et al., 2023;Nardou et al., 2023). However, the application of this neuroplasticity hypothesis in explaining the therapeutic mechanisms of psychedelics in humans is limited by the fact that neuroplasticity is an exceptionally broad concept, and encompasses a vast collection of physiological and computational processes comprising the dynamic system that is the brain. ...
Setting up a psychedelic study can be a long, arduous, and kafkaesque process. Researchers are faced with a host of challenges in this rapidly-evolving field, necessitating a range of questions that remain largely unstandardised. Many of the complexities inherent to psychedelic research also challenge existing assumptions around, for example, approaches to psychiatric prescribing, the conceptual framing of the placebo effect, and definitions of selfhood. This review paper aims to formalise these unique hurdles by addressing the sociocultural, political, legal, pharmacological, safety, study-design and experiential facets inherent to a psychedelic study. We bring several of the major psychedelic research teams across the United Kingdom, identify continuing areas of debate, and provide a practical, comprehensive, experience-based guide, with recommendations for policymakers and future researchers intending to set up a psychedelic research study or clinical trial.
... Its initial action is disinhibition of glutamate signaling at the NMDAR, preferentially inhibiting NMDARs on inhibitory GABAergic interneurons [50], leading to a paradoxical enhancement of glutamate release [51]. Glutamate activates postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), which in turn activate tropomyosin receptor kinase B (TrkB) for brain-derived neurotrophic factor (BDNF) to stimulate downstream synaptic protein synthesis and synaptogenesis [14,52]. ...
... The limited effect of ketamine on synaptic density in the CA1 of the hippocampus was unexpected, as ketamine is known to produce synaptic effects in the hippocampus [17,52,60]. In the mPFC, ketamine significantly increased synaptic density along with the postsynaptic protein PSD-95 but did not affect the presynaptic protein synapsin-1. ...
Background: Every year, over 40 million people sustain mild traumatic brain injury (mTBI) which affects the glucocorticoid stress pathway and synaptic plasticity. Ketamine, a multimodal dissociative anesthetic, modulates the stress pathway and synaptic plasticity. However, the effects of post-mTBI ketamine administration on plasma stress hormones and brain synaptic plasticity are largely unknown. Methods: Adult male Sprague-Dawley rats with indwelling jugular venous catheters sustained mTBI with the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA) in a single session (3 impacts × 1.5 J). One hour later, rats received intravenous (IV) ketamine (0, 10, or 20 mg/kg, 2 h). Catheter blood samples were collected for plasma corticosterone and progesterone assays. Brain tissue sections were double-labeled for presynaptic synapsin-1 and postsynaptic density protein 95 (PSD-95). Utilizing the Synaptic Evaluation and Quantification by Imaging Nanostructure (SEQUIN) workflow, super-resolution confocal images were generated, and synapsin-1, PSD-95, and synaptic density were quantified in the CA1 of the hippocampus and medial prefrontal cortex (mPFC). Results: IV ketamine infusion produced biphasic effects on corticosterone levels: a robust elevation during the infusion followed by a reduction after the infusion. CHIMERA injury elevated progesterone levels at post-injury day (PID)-1 and reduced synaptic density in the CA1 at PID-4, regardless of ketamine infusion. Ketamine infusion increased synaptic density in the mPFC at PID-4. Conclusions: Mild TBI and IV ketamine modulate the stress pathway and synaptic plasticity in the brain. Further research is warranted to investigate the functional outcomes of subanesthetic doses of ketamine on stress pathways and neuroplasticity following mTBI.
... slow down or prevent network disruption and the ensuing sensory and behavioral deficits. Hallucinogens, including ketamine and psilocybin, have received growing attention for their ability to promote synaptic and neuronal plasticity, and have been recognized as remarkably effective treatments for depression and substance use disorder (Berman et al., 2000;Aleksandrova and Phillips, 2021). It remains unclear whether their effects on mental health are related to their effects on neural plasticity. ...
... Because of these plasticitypromoting effects, ketamine and other hallucinogens have been recently characterized as psychoplastogens, a class of small molecules that rapidly promote plasticity following a single administration (Olson, 2018;Vargas et al., 2021;Pryazhnikov et al., 2018; but see Li et al., 2022). These effects may be due to ketamine's activation of the mammalian target of rapamycin (mTOR) pathway, which is involved in cell growth, autophagy, and synapse formation (Jaworski and Sheng, 2006;Hoeffer and Klann, 2010;Li et al., 2010;Phoumthipphavong et al., 2016;Aleksandrova and Phillips, 2021) but is inhibited in Alzheimer's transgenic mice and by Aß 42 (Ma et al., 2010). Second, the NMDA hypothesis is based on the hyperactivation of NMDA receptors by increased levels of soluble Aß 42 (Reisberg et al., 2003;Bezprozvanny and Mattson, 2008;Zhang et al., 2016), which contributes to excitotoxicity and synaptic dysfunction in Alzheimer's. ...
Ketamine has received growing attention for its effects on neuroplasticity and neuroinflammation, and as a treatment for depression and other mental health disorders. Recent evidence suggests that early sensory and behavioral deficits in Alzheimer's disease could be caused by synaptic disruption that occurs before irreversible neuropathology. This raises the possibility that ketamine could slow down or prevent network disruption and the ensuing sensory and behavioral deficits in Alzheimer's. Here we tested this idea in the 5XFAD mouse model of Alzheimer's, using either an acute single injection of ketamine, or chronic daily injections over 15 weeks. We tested the effects of ketamine on both amyloid plaque load and on a behavioral auditory gap detection task that is an early Alzheimer's biomarker in both mice and humans. We found that ketamine had no effect on plaque load, nor any effect on gap detection, for either acute or chronic dosing. Chronic ketamine facilitated startle responses specifically in 5XFAD mice, but this could simply be related to experience-dependent effects on stress or habituation rather than any rescue effect of ketamine on Alzheimer's-related deficits. We did find robust correlations between gap detection deficits and plaque load in auditory cortex and in the caudal pontine reticular nucleus, demonstrating that the behavioral deficits seen in 5XFAD mice are directly related to amyloid accumulation in these brain regions, and confirming the validity of gap detection as an early biomarker of Alzheimer's. Ketamine, however, had no effect on the strength of these correlations. We conclude that ketamine has no beneficial effect on the development of behavioral gap detection deficits or plaque load in the 5XFAD Alzheimer's mouse model, following either an acute single dose or a chronic daily dose regimen.
... Many stress-related psychiatric conditions, such as major depressive disorder (MDD), substance use disorder (SUD) and PTSD, have been associated with cortical atrophy, synaptic weakening and loss of connectivity, especially in the prefrontal cortex and hippocampus, consistent with dysregulation of neuroplasticity (46). A growing body of evidence from preclinical studies suggests that psychedelics may restore these pathological changes by inducing structural and synaptic plasticity (52). ...
... 5-HT2A receptors are typically coupled with Gq and β-arrestin, and the activation of these pathways can lead to production of brain-derived neurotrophic factor (BDNF) (58). Activation of presynaptic 5-HT2A receptors can lead to a glutamate burst resulting in subsequent activation of postsynaptic AMPA receptors engaging synaptogenic signalling cascades involving BDNF and mTOR (52). Binding of BDNF to its receptor, TrkB, activates signalling pathways including mTOR-mediated signalling, leading to neuritogenesis, spinogenesis and synaptogenesis (54). ...
Interest and academic research on psychedelics and psychedelic-assisted therapy in the treatment of psychiatric disorders has increased dramatically in the past two decades. In many ways, psychedelics represent a new therapeutic paradigm in the context of medicine. A key feature of psychedelics is their ability to reliably induce an altered experiential state, which is often described as mystical-like, self-transcending and meaningful, while also often experienced as challenging and anxiety-provoking. The subjective quality and content of the psychedelic experience has been consistently linked to their therapeutic effects. Here we review current understanding of the psychological and neurobiological mechanisms of psychedelics, as well as evidence of psychedelic-assisted therapy in the treatment of psychiatric conditions.
... 38,39 Ketamine potentially encourages neuroplasticity by triggering BDNF and mammalian target of rapamycin-mediated signaling, principally in the mesocorticolimbic DA system. [40][41][42] Rodent studies, for instance, have identified increased BDNF expression after ketamine administration in regions such as the medial prefrontal cortex (MPFC) and hippocampus. 43 The AMPAR activation facilitates structural plasticity enhancement of DA neurons and allows ketamine to enhance DA-induced motivation to pursue rewards. ...
... [44][45][46] Ketamine is also thought to increase the expression of synaptic proteins by targeting glutamate and serotonin receptors, which improves neural microstructure stability. 40 Ketamine was found to dampen hyperactivation in the subgenual ACC (sgACC) during feedback valence processing, potentially through rapidly reversing glutamatergic overactivation. 47 Given the direct relationship between sgACC hyperactivation and anticipatory anhedonia, ketamine's effect on sgACC holds special clinical relevance, indicating its antianhedonic mechanisms and its influence on reward sensitivity. ...
Ketamine is an N-methyl-D-aspartate receptor (NMDAR) antagonist that has shown effectiveness as a rapidly acting treatment for depression. Although advances have been made in understanding ketamine’s antidepressant pharmacological and molecular mechanisms of action, the large-scale neurocognitive mechanisms driving its therapeutic effects are less clearly understood. To help provide such a framework, we provide a synthesis of current evidence linking ketamine treatment to the modulation of brain systems supporting reward processing, interoception and self-related cognition. We suggest that ketamine’s antidepressant effects are, at least in part, driven by dynamic multi-level influences across these key functional domains.
... Both classic (LSD, 5-MeO-DMT, ayahuasca, mescaline, psilocybin) and non-classic substances (ibogaine, ketamine, MDMA), have been explored for the treatment of various SUDs with promising results [11,13]. Classic psychedelics interact with serotonin receptors, potentially impacting mood regulation and cognitive processes [15]. Non-classic psychedelics, with heterogeneous mechanisms including dopamine antagonism and N-methyl-D-aspartate (NMDA) agonism, may reduce dopamine levels in animal studies, impacting addiction's reward systems [1,8,[16][17][18]. ...
... On the other hand, classic psychedelics do not have as wide a mechanism of action as non-classic psychedelics but can also interact with other serotonin receptors, such as 5-HT2B and 5-HT2C [15,87]. Moreover, certain psychedelics may also affect serotonin receptors like 5-HT1, 5-HT6, and 5-HT7 [88,89]. ...
The current opioid crisis has had an unprecedented public health impact. Approved medications for opioid use disorder (OUD) exist, yet their limitations indicate a need for innovative treatments. Limited preliminary clinical studies suggest specific psychedelics might aid OUD treatment, though most clinical evidence remains observational, with few controlled trials. This review aims to bridge the gap between preclinical findings and potential clinical applications, following PRISMA-ScR guidelines. Searches included MEDLINE, Embase, Scopus, and Web of Science, focusing on preclinical in vivo studies involving opioids and psychedelics in animals, excluding pain studies and those lacking control groups. Forty studies met criteria, covering both classic and non-classic psychedelics. Most studies showed that 18-methoxycoronaridine (18-MC), ibogaine, noribogaine, and ketamine could reduce opioid self-administration, alleviate withdrawal symptoms, and change conditioned place preference. However, seven studies (two on 2,5-dimethoxy-4-methylamphetamine (DOM), three on ibogaine, one on 18-MC, and one on ketamine) showed no improvement over controls. A methodological quality assessment rated most of the studies as having unclear quality. Interestingly, most preclinical studies are limited to iboga derivatives, which were effective, but these agents may have higher cardiovascular risk than other psychedelics under-explored to date. This review strengthens support for translational studies testing psychedelics as potential innovative targets for OUD. It also suggests clinical studies need to include a broader range of agents beyond iboga derivatives but can also explore several ongoing questions in the field, such as the mechanism of action behind the potential therapeutic effect, safety profiles, doses, and frequency of administrations needed.
... Human imaging, postmortem analysis, and preclinical models all demonstrate that cortical atrophy is common in subjects exhibiting depressive phenotypes (14). Moreover, preclinical work in rodents has shown that chronic administration of selective-serotonin reuptake inhibitors (SSRIs) or a single administration of ketamine, psychedelics, or nonhallucinogenic psychoplastogens can induce cortical plasticity (15)(16)(17). However, given the challenges associated with measuring structural neuroplasticity non-invasively in a human brain, it has been difficult to find a translatable biomarker capable of detecting changes at the synaptic level. ...
... By focusing on phenotypic changes using a biomarker of structural neuroplasticity, the psychoplastogen field could embrace polypharmacology rather than prioritizing compounds based on efficacy at a single target. There are multiple receptors that lead to activation of cortical neuron growth pathways (16,17), and simultaneous targeting could have additive or synergistic effects. Moreover, a translatable biomarker of structural neuroplasticity like SV2A could be used to optimize drug dose and dosing frequency in humans. ...
Numerous preclinical studies have demonstrated that psychedelics promote the growth of cortical neurons in the prefrontal cortex. However, measuring psychedelic-induced structural plasticity in humans has remained a challenge. New advances in positron emission tomography imaging could facilitate the measurement of synaptic proteins in humans following psychedelic administration. Identifying a translatable biomarker of psychedelic-induced neuroplasticity would enable patient stratification and determination of optimal dosing paradigms while also facilitating the discovery of novel compounds that produce similar effects on structural neuroplasticity.
... These include structural and cellular alterations, such as neuronal loss and synaptic dysfunction, in cortico-limbic brain regions controlling mood and emotions (Kalivas and O'Brien, 2008;Manji et al., 2000). Thus, a framework is emerging around the idea that psychedelics may rectify these alterations by inducing a heightened state of plasticity which provides a window of opportunity for therapeutical intervention with enduring efficacy (Aleksandrova and Phillips, 2021;Castrén and Antila, 2017;Kavalali and Monteggia, 2020). ...
... Nevertheless, it appears that a mechanistically distinct ability to promote neuroplasticity that is unique in both intensity and kind may account for the difference in effect sizes and speed of response to psychedelics compared with currently available mental health medications. Although many reviews have explored the plasticitypromoting effects of psychedelics (Aleksandrova and Phillips, 2021;Calder and Hasler, 2023;Inserra et al., 2021;Liao et al., 2024;Olson, 2022;Slocum et al., 2022) , they predominantly focus on preclinical evidence, often neglecting translational validity and comprehensive cross-compound analysis. The purpose of this manuscript is to compare the available evidence about the impact of classic psychedelics, ketamine, and MDMA on neuroplasticity in both animal and human research. ...
Neuroplasticity, the ability of the nervous system to adapt throughout an organism's lifespan, offers potential as both a biomarker and treatment target for neuropsychiatric conditions. Psychedelics, a burgeoning category of drugs, are increasingly prominent in psychiatric research, prompting inquiries into their mechanisms of action. Distinguishing themselves from traditional medications, psychedelics demonstrate rapid and enduring therapeutic effects after a single or few administrations, believed to stem from their neuroplasticity-enhancing properties. This review examines how classic psychedelics (e.g., LSD, psilocybin, N,N-DMT) and non-classic psychedelics (e.g., ketamine, MDMA) influence neuroplasticity. Drawing from preclinical and clinical studies, we explore the molecular, structural, and functional changes triggered by these agents. Animal studies suggest psychedelics induce heightened sensitivity of the nervous system to environmental stimuli (meta-plasticity), re-opening developmental windows for long-term structural changes (hyper-plasticity), with implications for mood and behavior. Translating these findings to humans faces challenges due to limitations in current imaging techniques. Nonetheless, promising new directions for human research are emerging, including the employment of novel positron-emission tomography (PET) radioligands, non-invasive brain stimulation methods, and multimodal approaches. By elucidating the interplay between psychedelics and neuroplasticity, this review informs the development of targeted interventions for neuropsychiatric disorders and advances understanding of psychedelics' therapeutic potential.
... Moreover, although SP do not have direct affinity for glutamate (GLU) receptors, glutamatergic neurotransmission plays a significant role in their overall downstream effects. The activation by SP of postsynaptic serotonin 2 A receptors (5HT2AR) on pyramidal neurons leads to a GLU-dependent increase in the activity of neurons in the frontal cortex, subsequently modulating prefrontal network activity 16,17 . The resulting downstream signaling cascades involve ionotropic NMDAR and amino-3-hydroxy-5-methyl-isoxazolepropionic acid receptors (AMPAR) and increased AMPAR/NMDAR ratios 18 . ...
... The resulting downstream signaling cascades involve ionotropic NMDAR and amino-3-hydroxy-5-methyl-isoxazolepropionic acid receptors (AMPAR) and increased AMPAR/NMDAR ratios 18 . AMPAR activation may potentiate brain-derived neurotrophic factor-tropomyosin receptor kinase B (BDNF-TrkB) and mammalian target of rapamycin (mTOR) signaling, thus upregulating the expression of neuroplasticity-related genes and protein synthesis of synaptic components, ultimately leading to rapid and long-lasting synaptogenesis 7,17 . ...
The full therapeutic potential of serotonergic psychedelics (SP) in treating neuropsychiatric disorders, such as depression and schizophrenia, is limited by possible adverse effects, including perceptual disturbances and psychosis, which require administration in controlled clinical environments. This study investigates the synergistic benefits of combining psilocybin (PSIL) with N-methyl-D-aspartate receptor (NMDAR) modulators D-serine (DSER) and D-cycloserine (DCS) to enhance both efficacy and safety. Using ICR male mice, we examined head twitch response (HTR), MK-801-induced hyperlocomotion, and neuroplasticity related synaptic protein levels in the frontal cortex, hippocampus, amygdala, and striatum. Our results indicate that PSIL significantly increased HTR - a surrogate measure for hallucinogenic effects - which was reduced by the co-administration of DSER or DCS in a dose-dependent manner. Similarly, combining PSIL with DSER or DCS significantly decreased MK-801-induced hyperactivity, modeling antipsychotic effects. Neuroplasticity-related synaptic protein assays demonstrated that the PSIL-DSER combination enhanced GAP43 expression over all 4 brain examined and overall expression of the 4 assayed synaptic proteins in the hippocampus, while PSIL-DCS elevated PSD95 levels across all 4 brain regions, suggesting a synaptogenic synergy. These findings support the hypothesis that combinations of SP with NMDAR modulators could optimize the therapeutic potential of SP by mitigating adverse effects and enhancing neuroplasticity. Future studies should focus on refining administration protocols and evaluating translational applicability for broader clinical use.
... Psilocybin is structurally similar to N, N-dimethyltryptamine (DMT, a 5HT2A psychedelic). Both psilocybin and DMT [15] increased synaptic density [16], improved neuroplasticity [17,18], and showed anti-depressant [19] activity in experimental animals. The neuroplasticity action of DMT is associated with the expression of neurotrophins [18]. ...
... Both psilocybin and DMT [15] increased synaptic density [16], improved neuroplasticity [17,18], and showed anti-depressant [19] activity in experimental animals. The neuroplasticity action of DMT is associated with the expression of neurotrophins [18]. The TrkB (tyrosine receptor kinase B) inhibitor ANA12 or the mTOR inhibitor rapamycin antagonized DMT-mediated neuritogenesis or neuroplasticity in cortical neurons [15]. ...
Background
Psilocybin is a psychedelic 5HT2A receptor agonist found in “magic mushrooms”. Recent studies have indicated that 5HT2A agonists, such as dimethyltryptamine, given before middle cerebral artery occlusion (MCAo), improve staircase behavior, increased BDNF expression, and reduce brain infarction in stroke rats. The objective of this study is to determine the protective effect of psilocybin in cellular and animal models of stroke.
Methods
Adult male and timed-pregnant Sprague-Dawley rats were used for this study. The neural protective effects of psilocybin were determined in primary rat cortical neurons and adult rats. Rats were subjected to a 60-min middle cerebral artery occlusion. Brain tissues were collected for histological and qRTPCR analysis.
Results
Psilocybin reduced glutamate-mediated neuronal loss in rat primary cortical neuronal cultures. Psilocybin-mediated protection in culture was antagonized by the BDNF inhibitor ANA12. Pretreatment with psilocybin reduced brain infarction and neurological deficits in stroke rats. Early post-treatment with psilocybin improved locomotor behavior, upregulated the expression of MAP2 and synaptophysin, and down-regulated the expression of IBA1 in the stroke brain. ANA12 significantly attenuated psilocybin-mediated reduction in brain infarction and improvements in locomotor behavior.
Conclusions
Psilocybin reduced brain infarction and improved locomotor behavior in stroke rats; the protective mechanisms involve regulating BDNF expression. Our data support a novel therapeutic approach of psilocybin in stroke.
... These compounds were studied in both low-dose psychotherapy and psychedelic-assisted psychotherapy at varying doses, involving approximately 40 000 subjects [107]. Over time, the antidepressant properties of psilocybin have gained increasing recognition [48,49,[108][109][110][111]. ...
This systematic review examines the antidepressant potential of edible medicinal fungi (EMFs), focusing on their bioactive compounds and mechanisms of action. EMFs modulate neurotransmitter systems, including serotonin (5-HT) and dopamine (DA), alleviating depressive symptoms. Extracts from EMFs, such as Ganoderma lucidum, Hericium erinaceus, Poria cocos, and Cordyceps militaris, demonstrate significant antidepressant-like effects in preclinical studies. Their bioactive compounds influence the tryptophan-kynurenine (KYN) pathway, regulate the hypothalamus-pituitary-adrenal (HPA) axis, and reduce neuroinflammation, all of which are linked to stress response and mood regulation. The review also explores the gut-brain axis, highlighting how EMF-derived polysaccharides improve gut health by modulating microbiota, potentially mitigating depressive symptoms. Additionally, it discusses the use of EMFs in functional foods and dietary supplements, innovations like 3D food printing for depression-related issues, and synthetic biology for enhancing compound production. Artificial intelligence is used to model complex mechanisms. However, challenges remain, such as standardization and lack ofclinical validation. Future research should address these gaps, emphasizing personalized interventions and advanced technologies for next-generation antidepressant foods.
... [11][12][13][14] Ketamine has been shown to increase neuroplasticity, a marker associated with the improvement of mental health. [15][16][17] Abnormal or maladaptive neuroplasticity is implicated in multiple mental health disorders, such as depression and PTSD. 18 Ketamine is thought to "rewire" the brain and correct maladaptive neuroplasticity through its effects on brain-derived neurotrophic factor, mammalian target of rapamycin, and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. ...
... Even less information is available about putative nonpsychedelic analogues that are looked upon as potentially useful adjuncts to the current therapeutic options (Cameron et al., 2021;Lewis et al., 2023;Lu et al., 2021). Furthermore, given the neuroplastic effects of psychedelics (Aleksandrova and Phillips, 2021;Ly et al., 2018;Vargas et al., 2023), it is possible that even if they might not acutely elevate measurable improvements in the level of consciousness, they might have a sub-acute neuroplastic action that could facilitate rehabilitation, similarly to coadjuvant drugs. In this regard, the timing of both dosing and following rehabilitation is of cogent importance. ...
... In animal studies, antagonism of NMDA receptors in intermediate neurons of the forebrain and thalamus reduces GABAergic function. This action promotes the firing of layer V pyramidal neurons and stimulates glutamate release (Aleksandrova and Phillips, 2021), leading to excessive extracellular glutamate. This cascade can exacerbate neurodegeneration, particularly after chronic or high-dose administration (Liu et al., 2013). ...
The recreational abuse of addictive drugs poses considerable challenges to public health, leading to widespread neurotoxicity and neurological dysfunction. This review comprehensively examines the neurotoxic mechanisms, clinical manifestations, and treatment strategies associated with six commonly abused substances: methamphetamine, cocaine, synthetic cathinones, ketamine, nitrous oxide and heroin. Despite their diverse pharmacological properties, these drugs converge on shared neurotoxic pathways, including oxidative stress, mitochondrial dysfunction, excitotoxicity, and neuroinflammation. Psychostimulants, such as methamphetamine, cocaine and synthetic cathinones, disrupt monoaminergic neurotransmission, causing cognitive impairment, psychiatric disturbances, and neurovascular damage. Dissociative anesthetics, including ketamine and nitrous oxide, impair glutamatergic transmission and mitochondrial function, thereby exacerbating excitotoxicity and neuronal apoptosis. Opioids, such as heroin, primarily target the brain’s reward system and induce oxidative stress, neuroinflammation, and cerebrovascular complications. Treatment strategies remain limited, focusing on symptomatic management, neuroprotective interventions, and behavioral therapies. Emerging approaches, such as antioxidants, NMDA receptor modulators, and cognitive rehabilitation, show promise but require further validation. By highlighting the underlying mechanisms and therapeutic challenges, this review provides a foundation for developing targeted interventions and advancing research on drug-induced neurotoxicity.
... The exploration of specific signaling pathways, neurotransmitters (Kraus et al., 2017), and neurotrophic factors (Castrén and Monteggia, 2021) that influence neuroplasticity in specific brain regions, such as the cortical and limbic systems, has garnered significant attention. Encouraging findings from both animal and human studies indicate that novel rapid-acting antidepressants (i.e., ketamine) (Aleksandrova and Phillips, 2021), physical exercise (Vivar et al., 2012), or learning (Sagi et al., 2012) can enhance neuroplasticity, prompting further exploration and clinical application of promising neuroplasticitybased therapies. There is compelling evidence supporting the clinical efficacy of both manual acupuncture and electroacupuncture (EA) as complementary and integrative therapies for depression (Yang et al., 2022). ...
Major depressive disorder (MDD) is a highly prevalent and severely disabling psychiatric disorder that decreases quality of life and imposes substantial economic burden. Acupuncture has emerged as an effective adjunctive treatment for depression, it regulates neurotransmitters involved in mood regulation and modulates the activity of specific brain regions associated with emotional processing, as evidenced by neuroimaging and biochemical studies. Despite these insights, the precise neuroplastic mechanisms through which acupuncture exerts its antidepressant effects remain not fully elucidated. This review aims to summarize the current knowledge on acupuncture’s modulation of neuroplasticity in depression, with a focus on the neuroplasticity-based targets associated with acupuncture’s antidepressant effects. We encapsulate two decades of research into the neurobiological mechanisms underpinning the efficacy of acupuncture in treating depression. Additionally, we detail the acupoints and electroacupuncture parameters used in the treatment of depression to better serve clinical application.
... Ketamine is primarily an NMDA receptor antagonist 58 . Despite the distinct molecular targets, ketamine and psilocybin have similarities in their plasticity-promoting action and behavioral effects 59,60 , making ketamine an intriguing compound to contrast with psilocybin. The doses and route of administration for psilocybin and ketamine were chosen based on prior studies showing behavioral effects in mice 29,61 . ...
Psilocybin, ketamine, and MDMA are psychoactive compounds that exert behavioral effects with distinguishable but also overlapping features. The growing interest in using these compounds as therapeutics necessitates preclinical assays that can accurately screen psychedelics and related analogs. We posit that a promising approach may be to measure drug action on markers of neural plasticity in native brain tissues. We therefore developed a pipeline for drug classification using light sheet fluorescence microscopy of immediate early gene expression at cellular resolution followed by machine learning. We tested male and female mice with a panel of drugs, including psilocybin, ketamine, 5-MeO-DMT, 6-fluoro-DET, MDMA, acute fluoxetine, chronic fluoxetine, and vehicle. In one-versus-rest classification, the exact drug was identified with 67% accuracy, significantly above the chance level of 12.5%. In one-versus-one classifications, psilocybin was discriminated from 5-MeO-DMT, ketamine, MDMA, or acute fluoxetine with >95% accuracy. We used Shapley additive explanation to pinpoint the brain regions driving the machine learning predictions. Our results suggest a unique approach for characterizing and validating psychoactive drugs with psychedelic properties.
... A functional decoupling from SC is also what we observed, given the increased prevalence of fine-grained harmonics, which have been interpreted as reflecting a structurally decoupled signal. 83,96 Ketamine's similarity to classical psychedelics is further underscored by their shared ability to alter neuroplasticity, 129,130 induce similar phenomenology, 131 increase or maintain neurophysiologic complexity, 23,132 and expand the repertoire of functional brain activity models. 24,83 Other clear evidence of similarity between ketamine-induced unresponsiveness and states induced by classical psychedelics was given by Luppi and colleagues. ...
... An overarching phenomenon elucidated by preclinical studies and supported by neuroimaging data is that synaptic alterations in depression and those induced by chronic stress are maladaptive. A complementary aim of my independent research program therefore is to evaluate the potential of different types of compounds, which specifically enhance plasticity, to restore adaptive behavior (Duman et al., 2016;Martin and Nichols, 2018;Aleksandrova and Phillips, 2021;Parekh et al., 2022;Davoudian et al., 2023). Our ultimate hope is to identify commonly regulated signaling pathways which can be targeted for pharmacological, stimulation-based or behavioral therapeutic intervention and to better understand natural resilience. ...
Stressful experiences can affect both daily life and long-term health outcomes in a variety of ways. Acute challenges may be adaptive, promoting arousal and enhancing memory and cognitive function. Importantly, however, chronic stress dysregulates the body's physiological regulatory mechanisms consisting of complex hormone interactions throughout the peripheral and central nervous systems. This disrupted signaling consequently alters the balance of synapse formation, maturation and pruning, processes which regulate neural communication, plasticity, learning, cognitive flexibility and adaptive behaviors - hallmarks of a healthy, functional brain. The chronically stressed brain state, therefore, is one which may be uniquely vulnerable. To understand the development of this state, how it is sustained and how behavior and neural function are transiently or indelibly impacted by it, we can turn to a number of advanced approaches in animal models which offer unprecedented insights. This has been the aim of my recent work within the field and the goal of my new independent research program. To achieve this, I have employed methods to uncover how key brain circuits integrate information to support motivated behaviors, how stress impacts their ability to perform this process and how best to operationalize behavioral readouts. Here I present an overview of research contributions that I find most meaningful for advancing our understanding of the impact of stress and propose new avenues which will guide my own framework to address the salient outstanding questions within the field.
... Attempts to understand the downstream effects of ketamine have focused on the concept of neuroplasticity, suggesting the promotion of synaptogenesis and the 're-wiring' of pathological circuits in the brain [170,171]. Within this framework, lower doses of ketamine enhance neuroplasticity (2Ki), largely through the activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and neurotrophic signaling cascades, including the release of brain-derived neurotrophic factor (BDNF) and the activation of the mTOR pathway, which promote the growth of new synaptic connections and dendritic spines [172][173][174]. Much like the serotonergic psychedelics, ketamine's enhancement in neural plasticity is hypothesized to underlie ketamine's rapid antidepressant effects by potentially facilitating adaptive changes in brain circuitry that alleviate symptoms of depression [175]. ...
Introduction:
Since its synthesis in 1962, ketamine has been widely used in diverse medical contexts, from anesthesia to treatment-resistant depression. However, interpretations of ketamine's subjective effects remain polarized. Biomedical frameworks typically construe the drug's experiential effects as dissociative or psychotomimetic, while psychedelic paradigms emphasize the potential therapeutic merits of these non-ordinary states.
Areas covered:
Ketamine's psychoactive effects have inspired diverse interpretations. In this review, we trace the historical evolution of these perspectives - which we broadly categorize as 'dissociative,' 'dream-like,' and 'psychedelic' - and show how they emerged out of these clinical contexts. We highlight the influence of factors such as language, dose, and environmental context on ketamine's effects and therapeutic outcomes. We discuss potential mechanisms underlying these context-dependent effects and explore the broader clinical and research-related ramifications.
Expert opinion:
Ketamine's subjective effects are undeniably powerful, yet their therapeutic significance remains debated. A nuanced, interdisciplinary approach is essential for maximizing ketamine's potential. Future research should focus on how explanatory models, treatment environments, and patient preparation can optimize ketamine's benefits while minimizing distress. We suggest that, rather than being a tiger to be tamed as its creator once described, ketamine may best be understood as a chameleon whose color shifts depending on its context.
... This finding is supported by research in vitro, which demonstrated that psilocybin binds directly and with high affinity to the BDNF receptor TrkB (Moliner et al., 2023). In relation, studies in animals further revealed that psilocybin increase BDNF levels (Aleksandrova and Phillips, 2021;Banushi and Polito, 2023;de Vos et al., 2021). The elevation in BDNF observed in human studies is also in line with animal research reporting more direct effects on neuroplasticity following psilocybin administration including increased synaptic and dendritic spine density as well as increments in hippocampal neurogenesis along with reductions in antidepressant-like behaviour (Kim et al., 2024). ...
... Importantly, the between-group analysis of the study pointed to a better effect of ketamine on inner tension (MADRS_3) compared to midazolam at the end of treatment following repeated infusions, indicating potential superior anxiolytic efficacy of ketamine over midazolam, which is in line with previous research indicating assumed better efficacy of ketamine on stress-related depression [31]. Since inner tension often arises from unresolved emotional conflict, chronic stress, and underlying depression or anxiety, ketamine can play a crucial role in its reduction by modulating key neurotransmitter systems, promoting neuroplasticity, and disrupting maladaptive thought patterns [32][33][34]. Moreover, the majority of anxiety symptoms measured through clinicianadministered HAM-A significantly improved after the initial ketamine infusion, highlighting its rapid onset of anxiolytic effect consistent with the findings of previous studies [35][36][37][38][39]. ...
Background: Adolescent treatment resistant depression (TRD) is increasing in recent years. While ketamine showed rapid antidepressant effects in adult TRD studies, research on its effectiveness in adolescents is limited. Methods: This study examines the effects of intravenous ketamine vs. midazolam on depressive and anxiety symptomatology assessed by the Montgomery–Åsberg Depression Rating Scale (MADRS), Hamilton Anxiety Rating Scale (HAM-A), and Children’s Depression Inventory (CDI) at two time points—2 h after initial infusion (T0+2h) and 24 h after the end of the treatment (Te+24h) in a sample of 55 adolescent TRD females (27 receiving ketamine, 28 midazolam). Results: At T0+2h, within-group comparisons revealed a significant reduction in MADRS and HAM-A scores compared to baseline in the ketamine and midazolam groups. At Te+24h, both groups demonstrated similar significant reductions in MADRS, HAM-A, and CDI scores compared to baseline. The MADRS assessment in the ketamine group showed 33% and 59% responders, and in the midazolam group, 14% and 46% responders at T0+2h and Te+24h, respectively. HAM-A evaluation in the ketamine group revealed 33% and 56% responders, and in the midazolam group, 11% and 39% responders at T0+2h and at Te+24h, respectively. CDI rating discovered 11% and 44% responders in the ketamine group and 4% and 21% responders in the midazolam group at T0+2h and Te+24h, respectively. Moreover, inner tension significantly decreased in ketamine compared to the midazolam group at Te+24h. Conclusions: Ketamine showed a reduction in depressive and anxiety symptoms during a short-term period with particular efficacy in alleviating inner tension over midazolam, suggesting its potential advantages in specific symptom relief in rarely studied adolescent TRD.
... Additionally, we chose to analyze the effects of all known psychoplastogens together, given findings suggesting that they share downstream mechanisms of action involving glutamatergic signaling and remodeling of the extracellular matrix [20,100,101]. This is a similar approach to other meta-analyses analyzing multiple treatments expected to have similar effects on BDNF, for example antidepressant therapies [46][47][48]. ...
Background
Peripheral levels of brain-derived neurotrophic factor (BDNF) are often used as a biomarker for the rapid plasticity-promoting effects of ketamine, psychedelics, and other psychoplastogens in humans. However, studies analyzing peripheral BDNF after psychoplastogen exposure show mixed results. In this meta-analysis, we aimed to test whether the rapid upregulation of neuroplasticity seen in preclinical studies is detectable using peripheral BDNF in humans.
Methods
This analysis was pre-registered (PROSPERO ID: CRD42022333096) and funded by the University of Fribourg. We systematically searched PubMed, Web of Science, and PsycINFO to meta-analyze the effects of all available psychoplastogens on peripheral BDNF levels in humans, including ketamine, esketamine, LSD, psilocybin, ayahuasca, DMT, MDMA, scopolamine, and rapastinel. Risk of bias was assessed using Cochrane Risk of Bias Tools. Using meta-regressions and mixed effects models, we additionally analyzed the impact of several potential moderators.
Results
We included 29 studies and found no evidence that psychoplastogens elevate peripheral BDNF levels in humans (SMD = 0.024, p = 0.64). This result was not affected by drug, dose, blood fraction, participant age, or psychiatric diagnoses. In general, studies with better-controlled designs and fewer missing values reported smaller effect sizes. Later measurement timepoints showed minimally larger effects on BDNF.
Conclusion
These data suggest that peripheral BDNF levels do not change after psychoplastogen administration in humans. It is possible that peripheral BDNF is not an informative marker of rapid changes in neuroplasticity, or that preclinical findings on psychoplastogens and neuroplasticity may not translate to human subjects. Limitations of this analysis include the reliability and validity of BDNF measurement and low variation in some potential moderators. More precise methods of measuring rapid changes in neuroplasticity, including neuroimaging and stimulation-based methods, are recommended for future studies attempting to translate preclinical findings to humans.
... At the neuronal level, 5-HT 2A receptors are expressed on pyramidal neurons and interneurons. Notably, many brain regions with 5-HT 2A receptor expression, especially the PFC, hippocampus, and amygdala, are engaged in mood and memory [2]. The distribution of 5-HT 2A receptors in these brain regions supports the potential role of these receptors in mood disorders, suggesting the potential therapeutic effects of psychedelics on these psychiatric diseases (Fig. S2 online). ...
... Ketamine has indeed been observed to increase BDNF levels (Yang et al., 2013), increase spinogenesis and reverse dendritic atrophy (Li et al., 2010(Li et al., , 2011Moda-Sava et al., 2019), and produce fast and persistent antidepressant effects in patients and animal models (Berman et al., 2000;Browne and Lucki, 2013;Krystal et al., 2019;Murrough et al., 2013;Zarate et al., 2006). Psychedelics such as D-lysergic acid diethylamide (LSD), psilocybin, and dimethyltryptamine (DMT) have also been shown to promote neuroplasticity-possibly through a pathway that starts with serotonin 5-HT2A receptor agonism and involves stimulating BDNF production (Aleksandrova and Phillips, 2021;Calder and Hasler, 2023;Ly et al., 2018). They too can induce rapid antidepressant effects (dos Santos et al., 2016;Romeo et al., 2020;Rucker et al., 2016). ...
Deep Reinforcement Learning is a branch of artificial intelligence that uses artificial neural networks to model reward-based learning as it occurs in biological agents. Here we modify a Deep Reinforcement Learning approach by imposing a suppressive effect on the connections between neurons in the artificial network—simulating the effect of dendritic spine loss as observed in major depressive disorder (MDD). Surprisingly, this simulated spine loss is sufficient to induce a variety of MDD-like behaviors in the artificially intelligent agent, including anhedonia, increased temporal discounting, avoidance, and an altered exploration/exploitation balance. Furthermore, simulating alternative and longstanding reward-processing-centric conceptions of MDD (dysfunction of the dopamine system, altered reward discounting, context-dependent learning rates, increased exploration) does not produce the same range of MDD-like behaviors. These results support a conceptual model of MDD as a reduction of brain connectivity (and thus information-processing capacity) rather than an imbalance in monoamines—though the computational model suggests a possible explanation for the dysfunction of dopamine systems in MDD. Reversing the spine-loss effect in our computational MDD model can lead to rescue of rewarding behavior under some conditions. This supports the search for treatments that increase plasticity and synaptogenesis, and the model suggests some implications for their effective administration.
... As shown in Fig. 2F, LTP can be induced for at least 3 days following a single injection of Syn3. Similarly, dysregulation of neuroplasticity is implicated in depression [73], and ketamine, a long-lasting antidepressant drug that activates TrkB-mTOR signaling [74], restores the expression of neuroplasticity-related genes and protein synthesis via eEF2-mediated protein synthesis [75]. ...
... Notably, studies have indicated that chronic ketamine treatment can effectively counteract the decline in BDNF protein levels in critical regions such as the hippocampus and nucleus accumbens in a rat model of depression (204). These findings suggest that ketamine-induced BDNF release may facilitate the adaptive rewiring of pathological neurocircuitry, ultimately leading to enduring structural brain adaptations that can sustain therapeutic benefits even in the absence of chronic dosing (205). Moreover, it has been postulated that the rapid antidepressant effects of esketamine may be closely linked to synaptic potentiation, a phenomenon that could contribute to a reduction in negative thinking patterns (206). ...
Social cognitive deficits and social behavior impairments are common in major depressive disorder (MDD) and affect the quality of life and recovery of patients. This review summarizes the impact of standard and novel treatments on social functioning in MDD and highlights the potential of combining different approaches to enhance their effectiveness. Standard treatments, such as antidepressants, psychotherapies, and brain stimulation, have shown mixed results in improving social functioning, with some limitations and side effects. Newer treatments, such as intranasal oxytocin, mindfulness-based cognitive therapy, and psychedelic-assisted psychotherapy, have demonstrated positive effects on social cognition and behavior by modulating self-referential processing, empathy, and emotion regulation and through enhancement of neuroplasticity. Animal models have provided insights into the neurobiological mechanisms underlying these treatments, such as the role of neuroplasticity. Future research should explore the synergistic effects of combining different treatments and investigate the long-term outcomes and individual differences in response to these promising interventions.
... Ketamine demonstrates similar properties as a rapid-acting antidepressant (Corriger & Pickering, 2019). On a pharmacological level, these effects have been attributed to NMDA receptor antagonism and glutamate-driven changes in neuroplasticity (Aleksandrova & Phillips, 2021;Johnston et al., 2023;Vollenweider & Preller, 2020). ...
Dissociative therapies are being increasingly explored for their psychiatric applications, although questions remain about how they work and how best to use them. In exploring these questions, this review highlights six key areas of clinical relevance: (1) The possible contributions of functional unblinding when interpreting efficacy data; (2) The degree to which the therapeutic effects of dissociative therapies can be distinguished from the transient forms of relief seen with recreational drug use; (3) Understanding the construct of dissociation as it is tasked with describing the function of dissociative drugs; (4) The investigation of subjective drug effects as predictors of therapeutic outcome; (5) Similarities and differences in the effects of dissociative and classic psychedelics; and (6) The anticipated need for judicious prescribing/deprescribing resources as dissociative therapies proliferate.
... Glutamate is a key mediator of synaptic and neural plasticity, being involved in the phenomena of long-term potentiation (LTP) and inducing the release of brain-derived neurotrophic factor (BDNF) [72]. Indeed glutamate plays a pivotal role in the creation of long-lasting brain circuits [9,73], and, interestingly, psychedelics induce glutamate release particularly in frontal and prefrontal areas via stimulating 5-HT2A receptors on pyramidal cells in deep cortical layers, thus driving a frontal hypermetabolic state [74][75][76][77][78]. It is important to note that hypoactivity/hypometabolism of frontal and prefrontal areas is involved in the pathogenesis of schizophrenia (hypo-frontality) particularly affecting negative and cognitive symptoms [79][80][81]. ...
Psychedelics have shown promising effects in several psychiatric diseases as demonstrated by multiple clinical trials. However, no clinical experiments on patients with schizophrenia have been conducted up to date, except for some old semi-anecdotal studies mainly performed in the time-span '50s-'60s. Notably, these studies reported interesting findings, particularly on the improvement of negative symptoms and social cognition. With no doubts the lack of modern clinical studies is due to the psychomimetic properties of psychedelics, a noteworthy downside that could worsen positive symptoms. However, a rapidly increasing body of evidence has suggested that the mechanisms of action of such compounds partially overlaps with the pathogenic underpinnings of schizophrenia but in an opposite way. These findings suggest that, despite being a controversial issue, the use of psychedelics in the treatment of schizophrenia would be based on a strong biological rationale. Therefore, the aim of our perspective paper is to provide a background on the old experiments with psychedelics performed on patients with schizophrenia, interpreting them in the light of recent molecular findings on their ability to induce neuroplasticity and modulate connectivity, the immune and TAARs systems, neurotransmitters, and neurotropic factors. No systematic approach was adopted in reviewing the evidence given the difficulty to retrieve and interpret old findings. Interestingly, we identified a therapeutic potential of psychedelics in schizophrenia adopting a critical point of view, particularly on negative symptoms and social cognition, and we summarized all the relevant findings. We also identified an eligible subpopulation of chronic patients predominantly burdened by negative symptoms, outlining possible therapeutic strategies which encompass very low doses of psychedelics (microdosing), carefully considering safety and feasibility, to pave the way to future clinical trials.
... While the exact mechanisms by which ketamine works is unknown, the authors of the study hypothe-sized its effect to be mediated by synaptogenesis, which leads to the formation of new neuronal networks and the rewiring of dysfunctional circuits associated with depression (Kopelman et al. 2023). Furthermore, various preclinical studies demonstrated that ketamine regulates glutamatergic neurotransmission in the PFC, hippocampus, and other parts of the brain related to mood regulation (Aleksandrova and Phillips 2021). For instance, ketamine was shown to enhance the function of glutamate AMPA receptors in regions such as the medial prefrontal cortex (mPFC) (Björkholm et al. 2015) and hippocampus (El Iskandrani et al. 2015), thus enhancing synaptic strength and increasing excitatory neurotransmission. ...
Major depressive disorder (MDD) is a mental health disorder associated with cognitive impairment, dysregulated appetite, fatigue, insomnia or hypersomnia, and severe mood changes that significantly impact the ability of the affected individual to perform day-to-day tasks, leading to suicide in the worst-case scenario. As MDD is becoming more prevalent, affecting roughly 300 million individuals worldwide, its treatment has become a major point of interest. Antidepressants acting as selective serotonin reuptake inhibitors (SSRIs) are currently used as the first line of treatment for MDD. Other antidepressants currently used for the treatment of MDD include the serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs). However, although effective in alleviating symptoms of MDD, most antidepressants require weeks or even months of regular administration prior to eliciting a rational clinical effect. Owing to the strong evidence showing a relationship between neural plasticity, neurogenesis, and MDD, researchers have also looked at the possibility of using treatment modalities that target these processes in an attempt to improve clinical outcome. The overarching aim of this chapter is to highlight the role of neural plasticity and neurogenesis in the pathophysiology of MDD and discuss the most recently studied treatment strategies that target these processes by presenting supporting evidence from both animal and human studies.
... Combining our findings in ketamine with scopolamine, it became clear that the sustained antidepressant-like effects required the involvement of brain serotonergic neurotransmission. Furthermore, accumulating evidence suggested that neuroplasticity might underlie the sustained antidepressant-like effects of ketamine (Aleksandrova & Phillips, 2021;Fogaça et al., 2021). These results revealed that rapid release of glutamate in the mPFC induced by ketamine initiated the fast-acting behavioural effects, and long-lasting adaption in the serotonergic neurotransmission could maintain the antidepressant-like effects of ketamine. ...
Background and Purpose
The emerging antidepressant effects of ketamine have inspired tremendous interest in its underlying neurobiological mechanisms, although the involvement of 5‐HT in the antidepressant effects of ketamine remains unclear.
Experimental approach
The chronic restraint stress procedure was performed to induce depression‐like behaviours in mice. OFT, FST, TST, and NSFT tests were used to evaluate the antidepressant‐like effects of ketamine. Tph2 knockout or depletion of 5‐HT by PCPA and 5,7‐DHT were used to manipulate the brain 5‐HT system. ELISA and fibre photometry recordings were used to measure extracellular 5‐HT levels in the brain.
Key Results
60 min after injection, ketamine (10 mg·kg⁻¹, i.p.) produced rapid antidepressant‐like effects and increased brain 5‐HT levels. After 24 h, ketamine significantly reduced immobility time in TST and FST tests and increased brain 5‐HT levels, as measured by ELISA and fibre photometry recordings. The sustained (24 h) but not rapid (60 min) antidepressant‐like effects of ketamine were abrogated by PCPA and 5,7‐DHT, or by Tph2 knockout. Importantly, NBQX (10 mg·kg⁻¹, i.p.), an AMPA receptor antagonist, significantly inhibited the effect of ketamine on brain 5‐HT levels and abolished the sustained antidepressant‐like effects of ketamine in naïve or CRS‐treated mice.
Conclusion and Implications
This study confirms the requirement of serotonergic neurotransmission for the sustained antidepressant‐like effects of ketamine, which appears to involve AMPA receptors, and provides avenues to search for antidepressant pharmacological targets.
Depressive disorder (a subclass of mental disorders) is characterized by persistent affective symptoms. Without timely therapeutic intervention, it leads to clinical deterioration manifested as reduced quality of life and may increase suicide risk in severe cases. Given its complex etiology, intertwined with intrinsic factors such as genetics and environment, and impacted by various issues such as first-pass effect and blood-brain barrier, the therapeutic efficacy of many antidepressant medications is limited for patients. Therefore, by delving into the exploration of novel antidepressant drugs and biomaterials, this review aims to offer fresh perspectives that may facilitate the discovery of innovative antidepressant medications and enhance their therapeutic outcomes. Notably, the review highlights polymers’ crucial role in enhancing antidepressants’ pharmacological efficacy and pharmacokinetic properties by optimizing their parameters, and they will undoubtedly become powerful tools in improving antidepressive outcomes in future research.
Psychedelic compounds have gained renewed interest due to their rapid and long‐lasting therapeutic effects on stress‐related disorders. While the underlying mechanisms of therapeutic actions of psychedelic compounds are still unclear, these drugs are thought to modulate the activity of the serotonergic system, primarily through activating serotonin type 2A receptor (5‐HT 2A R) and studies have focused on these actions in the medial prefrontal cortex (mPFC). 25CN‐NBOH, a synthetic psychedelic compound with a high binding affinity for 5‐HT 2A Rs and anti‐anxiety actions, has emerged as a valuable tool for investigating the physiological functions mediated by this receptor. This study aimed to investigate the electrophysiological effects of 25CN‐NBOH on pyramidal mPFC neurons using whole‐cell patch clamp recordings in mouse brain slices. We recorded synaptic events and action potential rates during acute and long‐term exposure to two concentrations of 25CN‐NBOH. Acute application of 10 µM 25CN‐NBOH increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) that was reliant on activation of 5‐HT 2A R, and which was not seen upon chronic exposure. A similar effect of 200 nM 25CN‐NBOH was not noted. Surprisingly, both 10 µM and 200 nM 25CN‐NBOH significantly suppressed the firing rate following acute as well as a longer‐term exposure of 1 h. This suppression was independent of 5‐HT 2A R activation but was mediated by M‐current channels, as evidenced by the reversal of suppression with the M‐current blocker XE‐991. Our data suggest a complicated dual action of 25CN‐NBOH in enhancing excitatory transmission while also reducing excitability. Our data contribute to knowledge regarding the cellular consequence of 5‐HT 2A R agonism and contribute to widening our understanding of the potential mechanisms underlying the therapeutic actions of serotonergic psychedelics.
Background/Objectives: Non-response to initial treatment options for major depressive disorder (MDD) is a common clinical challenge with profound deleterious impacts for affected patients. Few treatments have received regulatory approval for treatment-resistant depression (TRD). Methods: A systematic search of United States and European Union clinical trials registries was conducted to identify Phase II, III, or IV clinical trials, with a last update posted on or after 1 January 2020, that were evaluating medications for TRD. For both the US and EU registries, the condition term “treatment resistant depression” and associated lower-level terms (per registry search protocol) were used. For the US registry, a secondary search using the condition term “depressive disorders” and the modifying term “inadequate” was also performed to capture registrations not tagged as TRD. Two additional searches were also conducted in the US registry for the terms “suicide” and “anhedonia” as transdiagnostic targets of investigational medications. Trials were categorized based on the primary mechanism of action of the trial’s investigational medication. Results: Fifty clinical trials for TRD, 20 for anhedonia, and 25 for suicide were identified. Glutamate system modulation was the mechanism currently with the most compounds in development, including antagonists and allosteric modulators of NMDA receptors, AMPA receptors, metabotropic type 2/3 glutamate receptors, and intracellular effector molecules downstream of glutamate signaling. Psychedelics have seen the greatest surge among mechanistic targets in the past 5 years, however, with psilocybin in particular garnering significant attention. Other mechanisms included GABA modulators, monoamine modulators, anti-inflammatory/immune-modulating agents, and an orexin type 2 receptor antagonist. Conclusions: These investigations offer substantial promise for more efficacious and potentially personalized medication approaches for TRD. Challenges for detecting efficacy in TRD include the heterogeneity within the TRD population stemming from the presumed variety of biological dysfunctions underlying the disorder, comorbid disorders, chronic psychosocial stressors, and enduring effects of prior serotonergic antidepressant medication treatments.
Zusammenfassung
Hintergrund
Neue antidepressive Substanzen stellen die Erklärungsansätze zu Wirkmechanismen der traditionellen Psychopharmakologie vor Herausforderungen.
Fragestellung
Was könnten gemeinsame Effekte der verschiedenen Antidepressiva sein und welche Rolle spielen dabei jeweils extrapharmakologische Faktoren wie Körper und Umwelt?
Material und Methode
Die verfügbare Literatur über klinische und präklinische Daten zu vermuteten gemeinsamen Wirkfaktoren von serotonergen Psychedelika, (Es‑)Ketamin, monoaminergen Antidepressiva und Zuranolon wird dargestellt und der Einfluss von Kontextfaktoren auf die jeweiligen Wirkmechanismen diskutiert.
Ergebnisse
Es deutet vieles darauf hin, dass klassischere und neuere pharmakologische Ansätze der Depressionsbehandlung ähnliche Wirkmechanismen teilen könnten. Diese Mechanismen begünstigen langfristige Neuroplastizität, die nachgeschaltete molekulare Kaskaden auslösen können und vice versa. Darüber hinaus wurde für die meisten antidepressiven Substanzen auch eine Verbesserung der negativen Verzerrung in der emotionalen Verarbeitung nachgewiesen. Der Einfluss extrapharmakologischer Faktoren scheint notwendig zu sein, damit die biopsychologischen Veränderungen antidepressiv wirksam sein können.
Schlussfolgerungen
Anstatt Faktoren wie Umwelt, Körper und soziale Interaktionen zu den Placeboeffekten zu zählen, sollten sie als essenzieller Baustein der antidepressiven Wirkung geprüft und in der klinischen Versorgung mitbedacht werden.
Hesperidin treatments reduce depressive symptoms in mouse models of depression, but the mechanism that mediates its antidepressant effects is unclear. This study shows that hesperidin exerts its antidepressant effects by activating α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor to promote synaptic and neuronal function in the hippocampus. The optimal dose of hesperidin (10 mg/kg) for the antidepressant potential was determined after 7 consecutive days of treatments, demonstrating decreased latency to eat and increased food consumption in novelty suppressed feeding, and decreased immobility time in tail suspension test (TST). Moreover, the optimal dose also reversed the depressive phenotypes of Institute of Cancer Research mice exposed to chronic unpredictable mild stress (CUMS), including reduced immobility time in the TST and increased sucrose preference in the sucrose preference test. In addition, hesperidin increased the expression of AMPA receptor protein (Glur1) and synaptic proteins (BDNF, PSD95, synapsin1) in the hippocampus of CUMS-exposed mice. Furthermore, inhibition of AMPA receptor activity by NBQX blocked the effect of hesperidin in reversing the depressive phenotypes, upregulated the expression of synaptic proteins (BDNF, PSD95, synapsin1) and cFOS-positive cells in the hippocampus, and increased the number of Ki67-positive cells in the dentate gyrus of the hippocampus of CUMS-exposed mice. These results help to further understand the antidepressant mechanism of hesperidin and provide new ideas for the future development of antidepressant drugs.
Substance use disorder (SUD) is common in psychiatric patients and has a negative impact on health and well-being. However, SUD often goes untreated, and there is a need for psychiatrists, of all specialties, to address this pervasive clinical problem. In this review, the authors' goal is to provide a resource that describes treatments for SUD, using neuroscience as a framework. They discuss the effect of pharmacotherapy on craving, intoxication, and withdrawal and its ability to interrupt the cycle of substance use in SUD. The neuroscience of stress is reviewed, including medications targeting neurotransmitter systems activated by alarm and fear. Neuroplasticity and promising treatments that use this mechanism, including ketamine, psilocybin, and transcranial magnetic stimulation (TMS), are discussed. The authors conclude by listing resources and practice guidelines for physicians interested in learning more about treatments for SUD.
Background:
Psychedelic substance use in ritualistic and ceremonial settings dates back as early as 8,500 BCE. Only in recent years, from the mid-20th century, we have seen the re-emergence of psychedelics in a therapeutic setting and more specifically for the treatment of addiction. This article aims to review research over the past 40 years using classic (psilocybin, lysergic acid diethylamide [LSD], dimethyltryptamine [DMT], mescaline) and atypical (ketamine, ibogaine, 5-MeO-DMT, 3,4-methylenedioxymethamphetamine) psychedelics for the treatment of addiction.
Summary:
We will start with an overview of the pharmacology and physiological and psychological properties of psychedelic substances from pre-clinical and clinical research. We will then provide an overview of evidence gathered by studies conducted in controlled research environments and naturalistic and ceremonial settings, while we identify the proposed therapeutic mechanisms of each psychedelic substance.
Key messages:
Classic and atypical psychedelics show promise as therapeutic alternatives for the treatment of addiction, through the improvement of psychological and physiological symptoms of dependence. A more comprehensive understanding of the ancient and present-day knowledge of the therapeutic potential of psychedelics can facilitate hope for psychedelic therapeutics in the treatment of addiction, especially for individuals who have failed other conventional treatment methods.
Ketamine produces a rapid antidepressant response in patients with major depressive disorder (MDD), but the underlying mechanisms appear multifaceted. One hypothesis, proposes that by antagonizing NMDA receptors on GABAergic interneurons, ketamine disinhibits afferens to glutamatergic principal neurons and increases extracellular glutamate levels. However, ketamine seems also to reduce rapid glutamate release at some synapses. Therefore, clinical studies in MDD patients have stressed the need to identify mechanisms whereby ketamine decreases presynaptic activity and glutamate release. In the present study, the effect of ketamine and its antidepressant metabolite, (2R,6R)-HNK, on neuronally derived glutamate release was examined in rodents. We used FAST methodology to measure depolarization-evoked extracellular glutamate levels in vivo in freely moving or anesthetized animals, synaptosomes to detect synaptic recycling ex vivo and primary cortical neurons to perform functional imaging and to examine intracellular signaling in vitro. In all these versatile approaches, ketamine and (2R,6R)-HNK reduced glutamate release in a manner which could be blocked by AMPA receptor antagonism. Antagonism of adenosine A1 receptors, which are almost exclusively expressed at nerve terminals, also counteracted ketamine’s effect on glutamate release and presynaptic activity. Signal transduction studies in primary neuronal cultures demonstrated that ketamine reduced P-T286-CamKII and P-S9-Synapsin, which correlated with decreased synaptic vesicle recycling. Moreover, systemic administration of A1R antagonist counteracted the antidepressant-like actions of ketamine and (2R,6R)-HNK in the forced swim test. To conclude, by studying neuronally released glutamate, we identified a novel retrograde adenosinergic feedback mechanism that mediate inhibitory actions of ketamine on glutamate release that may contribute to its rapid antidepressant action.
Psilocybin is a serotonergic psychedelic with untapped therapeutic potential. There are hints that the use of psychedelics can produce neural adaptations, although the extent and timescale of the impact in a mammalian brain are unknown. In this study, we used chronic two-photon microscopy to image longitudinally the apical dendritic spines of layer 5 pyramidal neurons in the mouse medial frontal cortex. We found that a single dose of psilocybin led to ∼10% increases in spine size and density, driven by an elevated spine formation rate. The structural remodeling occurred quickly within 24 h and was persistent 1 month later. Psilocybin also ameliorated stress-related behavioral deficit and elevated excitatory neurotransmission. Overall, the results demonstrate that psilocybin-evoked synaptic rewiring in the cortex is fast and enduring, potentially providing a structural trace for long-term integration of experiences and lasting beneficial actions.
The rapidly acting antidepressants ketamine and scopolamine exert behavioral effects that can last from several days to more than a week in some patients. The molecular mechanisms underlying the maintenance of these antidepressant effects are unknown. Here we show that methyl-CpG-binding protein 2 (MeCP2) phosphorylation at Ser421 (pMeCP2) is essential for the sustained, but not the rapid, antidepressant effects of ketamine and scopolamine in mice. Our results reveal that pMeCP2 is downstream of BDNF, a critical factor in ketamine and scopolamine antidepressant action. In addition, we show that pMeCP2 is required for the long-term regulation of synaptic strength after ketamine or scopolamine administration. These results demonstrate that pMeCP2 and associated synaptic plasticity are essential determinants of sustained antidepressant effects. How ketamine and scopolamine produce sustained antidepressant effects remains unknown. Kim et al. show that BDNF-dependent MeCP2 phosphorylation drives sustained antidepressant effects of ketamine and scopolamine with distinct synaptic plasticity changes.
The high symptomatic and biological heterogeneity of major depressive disorder (MDD) makes it very difficult to find broadly efficacious treatments that work against all symptoms. Concentrating on single core symptoms that are biologically well understood might consist of a more viable approach. The Research Domain Criteria (RDoC) framework is a trans-diagnostic dimensional approach that focuses on symptoms and their underlying neurobiology. Evidence is accumulating that psychedelics may possess antidepressant activity, and this can potentially be explained through a multi-level (psychobiological, circuitry, (sub)cellular and molecular) analysis of the cognitive systems RDoC domain. Cognitive deficits, such as negative emotional processing and negativity bias, often lead to depressive rumination. Psychedelics can increase long-term cognitive flexibility, leading to normalization of negativity bias and reduction in rumination. We propose a theoretical model that explains how psychedelics can reduce the negativity bias in depressed patients. At the psychobiological level, we hypothesize that the negativity bias in MDD is due to impaired pattern separation and that psychedelics such as psilocybin help in depression because they enhance pattern separation and hence reduce negativity bias. Pattern separation is a mnemonic process that relies on adult hippocampal neurogenesis, where similar inputs are made more distinct, which is essential for optimal encoding of contextual information. Impairment in this process may underlie the negative cognitive bias in MDD by, for example, increased pattern separation of cues with a negative valence that can lead to excessive deliberation on aversive outcomes. On the (sub) cellular level, psychedelics stimulate hippocampal neurogenesis as well as synaptogenesis, spinogenesis and dendritogenesis in the prefrontal cortex. Together, these effects help restoring resilience to chronic stress and lead to modulation of the major connectivity hubs of the prefrontal cortex, hippocampus, and amygdala. Based on these observations, we propose a new translational framework to guide the development of a novel generation of therapeutics to treat the cognitive symptoms in MDD.
Long term benefits following short-term administration of high psychedelic doses of serotonergic and dissociative hallucinogens, typified by psilocybin and ketamine respectively, support their potential as treatments for psychiatric conditions such as major depressive disorder. The high psychedelic doses induce perceptual experiences which are associated with therapeutic benefit. There have also been anecdotal reports of these drugs being used at what are colloquially referred to as “micro” doses to improve mood and cognitive function, although currently there are recognized limitations to their clinical and preclinical investigation. In the present studies we have defined a low dose and plasma exposure range in rats for both ketamine (0.3–3 mg/kg [10–73 ng/ml]) and psilocybin/psilocin (0.05–0.1 mg/kg [7–12 ng/ml]), based on studies which identified these as sub-threshold for the induction of behavioral stereotypies. Tests of efficacy were focused on depression-related endophenotypes of anhedonia, amotivation and cognitive dysfunction using low performing male Long Evans rats trained in two food motivated tasks: a progressive ratio (PR) and serial 5-choice (5-CSRT) task. Both acute doses of ketamine (1–3 mg/kg IP) and psilocybin (0.05–0.1 mg/kg SC) pretreatment increased break point for food (PR task), and improved attentional accuracy and a measure of impulsive action (5-CSRT task). In each case, effect size was modest and largely restricted to test subjects characterized as “low performing”. Furthermore, both drugs showed a similar pattern of effect across both tests. The present studies provide a framework for the future study of ketamine and psilocybin at low doses and plasma exposures, and help to establish the use of these lower concentrations of serotonergic and dissociative hallucinogens both as a valid scientific construct, and as having a therapeutic utility.
Clinical studies have reported that the psychedelic lysergic acid diethylamide (LSD) enhances empathy and social behavior (SB) in humans, but its mechanism of action remains elusive. Using a multidisciplinary approach including in vivo electrophysiology, optogenetics, behavioral paradigms, and molecular biology, the effects of LSD on SB and glutamatergic neurotransmission in the medial prefrontal cortex (mPFC) were studied in male mice. Acute LSD (30 μg/kg) injection failed to increase SB. However, repeated LSD (30 μg/kg, once a day, for 7 days) administration promotes SB, without eliciting antidepressant/anxiolytic-like effects. Optogenetic inhibition of mPFC excitatory neurons dramatically inhibits social interaction and nullifies the prosocial effect of LSD. LSD potentiates the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and 5-HT2A, but not N-methyl-D-aspartate (NMDA) and 5-HT1A, synaptic responses in the mPFC and increases the phosphorylation of the serine-threonine protein kinases Akt and mTOR. In conditional knockout mice lacking Raptor (one of the structural components of the mTORC1 complex) in excitatory glutamatergic neurons (Raptor
f/f
:Camk2alpha-Cre), the prosocial effects of LSD and the potentiation of 5-HT2A/AMPA synaptic responses were nullified, demonstrating that LSD requires the integrity of mTORC1 in excitatory neurons to promote SB. Conversely, in knockout mice lacking Raptor in GABAergic neurons of the mPFC (Raptor
f/f
:Gad2-Cre), LSD promotes SB. These results indicate that LSD selectively enhances SB by potentiating mPFC excitatory transmission through 5-HT2A/AMPA receptors and mTOR signaling. The activation of 5-HT2A/AMPA/mTORC1 in the mPFC by psychedelic drugs should be explored for the treatment of mental diseases with SB impairments such as autism spectrum disorder and social anxiety disorder.
A single dose of psilocybin, a psychedelic and serotonin 2A receptor (5-HT2AR) agonist, may be associated with antidepressant effects. The mechanism behind its antidepressive action is unknown but could be linked to increased synaptogenesis and down-regulation of cerebral 5-HT2AR. Here, we investigate if a single psychedelic dose of psilocybin changes synaptic vesicle protein 2A (SV2A) and 5-HT2AR density in the pig brain. Twenty-four awake pigs received either 0.08 mg/kg psilocybin or saline intravenously. Twelve pigs (n = 6/intervention) were euthanized one day post-injection, while the remaining twelve pigs were euthanized seven days post-injection (n = 6/intervention). We performed autoradiography on hippocampus and prefrontal cortex (PFC) sections with [³H]UCB-J (SV2A), [³H]MDL100907 (5-HT2AR antagonist) and [³H]Cimbi-36 (5-HT2AR agonist). One day post psilocybin injection, we observed 4.42% higher hippocampal SV2A density and lowered hippocampal and PFC 5-HT2AR density (−15.21% to −50.19%). These differences were statistically significant in the hippocampus for all radioligands and in the PFC for [³H]Cimbi-36 only. Seven days post-intervention, there was still significantly higher SV2A density in the hippocampus (+9.24%) and the PFC (+6.10%), whereas there were no longer any differences in 5-HT2AR density. Our findings suggest that psilocybin causes increased persistent synaptogenesis and an acute decrease in 5-HT2AR density, which may play a role in psilocybin’s antidepressive effects.
Rationale
Major depressive disorder is one of the leading global causes of disability, for which the classic serotonergic psychedelics have recently reemerged as a potential therapeutic treatment option.
Objective
We present the first meta-analytic review evaluating the clinical effects of classic serotonergic psychedelics vs placebo for mood state and symptoms of depression in both healthy and clinical populations (separately).
Results
Our search revealed 12 eligible studies ( n = 257; 124 healthy participants, and 133 patients with mood disorders), with data from randomized controlled trials involving psilocybin ( n = 8), lysergic acid diethylamide ([LSD]; n = 3), and ayahuasca ( n = 1). The meta-analyses of acute mood outcomes (3 h to 1 day after treatment) for healthy volunteers and patients revealed improvements with moderate significant effect sizes in favor of psychedelics, as well as for the longer-term (16 to 60 days after treatments) mood state of patients. For patients with mood disorder, significant effect sizes were detected on the acute, medium (2–7 days after treatment), and longer-term outcomes favoring psychedelics on the reduction of depressive symptoms.
Conclusion
Despite the concerns over unblinding and expectancy, the strength of the effect sizes, fast onset, and enduring therapeutic effects of these psychotherapeutic agents encourage further double-blind, placebo-controlled clinical trials assessing them for management of negative mood and depressive symptoms.
Background
Ketamine elicits rapid onset antidepressant effects in clinically depressed patients, through mechanisms hypothesized to involve the genesis of neocortical dendritic spines and synapses. Yet, the observed changes in dendritic spine morphology usually emerge well after ketamine clearance, raising questions about the link between rapid behavioral effects of ketamine and plasticity.
Methods
Here, we use 2-photon glutamate uncaging/imaging to focally induce spinogenesis in the medial prefrontal cortex (mPFC), directly interrogating baseline and ketamine-associated plasticity of deep layer pyramidal neurons in C57BL/6 mice. We combine pharmacological, genetic, optogenetic, and chemogenetic manipulations to interrogate dopaminergic mechanisms underlying ketamine-induced rapid enhancement in evoked plasticity and associated behavioral changes.
Results
We find that ketamine rapidly enhances glutamate-evoked spinogenesis in mPFC, with timing that matches the onset of its behavioral efficacy and precedes changes in dendritic spine density. Ketamine increases evoked cortical spinogenesis through Drd1 receptor activation that requires dopamine release, compensating blunted plasticity in a learned helplessness paradigm. The enhancement in evoked spinogenesis after Drd1 activation or ketamine treatment depends on postsynaptic Protein Kinase A (PKA) activity. Furthermore, ketamine’s behavioral effects are blocked by chemogenetic inhibition of dopamine release and mimicked by activating presynaptic dopaminergic terminals, or postsynaptic Gαs-coupled cascades in mPFC.
Conclusions
Our findings highlight dopaminergic mediation of rapid enhancement in activity-dependent dendritic spinogenesis and behavioral effects induced by ketamine.
Mounting evidence suggests safety and efficacy of psychedelic compounds as potential novel therapeutics in psychiatry. Ketamine has been approved by the Food and Drug Administration in a new class of antidepressants, and 3,4-methylenedioxymethamphetamine (MDMA) is undergoing phase III clinical trials for post-traumatic stress disorder. Psilocybin and lysergic acid diethylamide (LSD) are being investigated in several phase II and phase I clinical trials. Hence, the concept of psychedelics as therapeutics may be incorporated into modern society. Here, we discuss the main known neurobiological therapeutic mechanisms of psychedelics, which are thought to be mediated by the effects of these compounds on the serotonergic (via 5-HT2A and 5-HT1A receptors) and glutamatergic [via N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors] systems. We focus on 1) neuroplasticity mediated by the modulation of mammalian target of rapamycin–, brain-derived neurotrophic factor–, and early growth response–related pathways; 2) immunomodulation via effects on the hypothalamic-pituitary-adrenal axis, nuclear factor ĸB, and cytokines such as tumor necrosis factor-α and interleukin 1, 6, and 10 production and release; and 3) modulation of serotonergic, dopaminergic, glutamatergic, GABAergic, and norepinephrinergic receptors, transporters, and turnover systems. We discuss arising concerns and ways to assess potential neurobiological changes, dependence, and immunosuppression. Although larger cohorts are required to corroborate preliminary findings, the results obtained so far are promising and represent a critical opportunity for improvement of pharmacotherapies in psychiatry, an area that has seen limited therapeutic advancement in the last 20 years. Studies are underway that are trying to decouple the psychedelic effects from the therapeutic effects of these compounds.
Significance Statement
Psychedelic compounds are emerging as potential novel therapeutics in psychiatry. However, understanding of molecular mechanisms mediating improvement remains limited. This paper reviews the available evidence concerning the effects of psychedelic compounds on pathways that modulate neuroplasticity, immunity, and neurotransmitter systems. This work aims to be a reference for psychiatrists who may soon be faced with the possibility of prescribing psychedelic compounds as medications, helping them assess which compound(s) and regimen could be most useful for decreasing specific psychiatric symptoms.
Background
The glutamatergic modulator ketamine has created a blueprint for studying novel pharmaceuticals in the field. Recent studies suggest that “classic” serotonergic psychedelics (SPs) may also have antidepressant efficacy. Both ketamine and SPs appear to produce rapid, sustained antidepressant effects after a transient psychoactive period.
Methods
This review summarizes areas of overlap between SP and ketamine research and considers the possibility of a common, downstream mechanism of action. The therapeutic relevance of the psychoactive state, overlapping cellular and molecular effects, and overlapping electrophysiological and neuroimaging observations are all reviewed.
Results
Taken together, the evidence suggests a potentially shared mechanism wherein both ketamine and SPs may engender rapid neuroplastic effects in a glutamatergic activity-dependent manner. It is postulated that, though distinct, both ketamine and SPs appear to produce acute alterations in cortical network activity that may initially produce psychoactive effects and later produce milder, sustained changes in network efficiency associated with therapeutic response. However, despite some commonalities between the psychoactive component of these pharmacologically distinct therapies—such as engagement of the downstream glutamatergic pathway—the connection between psychoactive impact and antidepressant efficacy remains unclear and requires more rigorous research.
Conclusions
Rapid-acting antidepressants currently under investigation may share some downstream pharmacological effects, suggesting that their antidepressant effects may come about via related mechanisms. Given the prototypic nature of ketamine research and recent progress in this area, this platform could be used to investigate entirely new classes of antidepressants with rapid and robust actions.
A revamped interest in the study of hallucinogens has recently emerged, especially with regard to their potential application in the treatment of psychiatric disorders. In the last decade, a plethora of preclinical and clinical studies have confirmed the efficacy of ketamine in the treatment of depression. More recently, emerging evidence has pointed out the potential therapeutic properties of psilocybin and LSD, as well as their ability to modulate functional brain connectivity. Moreover, MDMA, a compound belonging to the family of entactogens, has been demonstrated to be useful to treat post-traumatic stress disorders. In this review, the pharmacology of hallucinogenic compounds is summarized by underscoring the differences between psychedelic and nonpsychedelic hallucinogens as well as entactogens, and their behavioral effects in both animals and humans are described. Together, these data substantiate the potentials of these compounds in treating mental diseases.
Growing interest has been seen in using lysergic acid diethylamide (LSD) in psychiatric research and therapy. However, no modern studies have evaluated subjective and autonomic effects of different and pharmaceutically well-defined doses of LSD. We used a double-blind, randomized, placebo-controlled, crossover design in 16 healthy subjects (eight women, eight men) who underwent six 25 h sessions and received placebo, LSD (25, 50, 100, and 200 µg), and 200 µg LSD 1 h after administration of the serotonin 5-hydroxytryptamine-2A (5-HT2A) receptor antagonist ketanserin (40 mg). Test days were separated by at least 10 days. Outcome measures included self-rating scales that evaluated subjective effects, autonomic effects, adverse effects, plasma brain-derived neurotrophic factor levels, and pharmacokinetics up to 24 h. The pharmacokinetic-subjective response relationship was evaluated. LSD showed dose-proportional pharmacokinetics and first-order elimination and dose-dependently induced subjective responses starting at the 25 µg dose. A ceiling effect was observed for good drug effects at 100 µg. The 200 µg dose of LSD induced greater ego dissolution than the 100 µg dose and induced significant anxiety. The average duration of subjective effects increased from 6.7 to 11 h with increasing doses of 25–200 µg. LSD moderately increased blood pressure and heart rate. Ketanserin effectively prevented the response to 200 µg LSD. The LSD dose–response curve showed a ceiling effect for subjective good effects, and ego dissolution and anxiety increased further at a dose above 100 µg. These results may assist with dose finding for future LSD research. The full psychedelic effects of LSD are primarily mediated by serotonin 5-HT2A receptor activation.
Renewed interest in the use of psychedelics in the treatment of psychiatric disorders warrants a better understanding of the neurobiological mechanisms underlying the effects of these substances. After a hiatus of about 50 years, state-of-the art studies have recently begun to close important knowledge gaps by elucidating the mechanisms of action of psychedelics with regard to their effects on receptor subsystems, systems-level brain activity and connectivity, and cognitive and emotional processing. In addition, functional studies have shown that changes in self-experience, emotional processing and social cognition may contribute to the potential therapeutic effects of psychedelics. These discoveries provide a scientific road map for the investigation and application of psychedelic substances in psychiatry.
Accumulating evidence implicates dysregulation of hippocampal synaptic plasticity in the pathophysiology of depression. However, the effects of ketamine on synaptic plasticity and their contribution to its mechanism of action as an antidepressant, are still unclear. We investigated ketamine's effects on in vivo dorsal hippocampal (dHPC) synaptic plasticity and their role in mediating aspects of antidepressant activity in the Wistar-Kyoto (WKY) model of depression. dHPC long-term potentiation (LTP) was significantly impaired in WKY rats compared to Wistar controls. Importantly, a single low dose (5 mg/kg, ip) of ketamine or its metabolite, (2R,6R)-HNK, rescued the LTP deficit in WKY rats at 3.5 h but not 30 min following injection, with residual effects at 24 h, indicating a delayed, sustained facilitatory effect on dHPC synaptic plasticity. Consistent with the observed dHPC LTP deficit, WKY rats exhibited impaired hippocampal-dependent long-term spatial memory as measured by the novel object location recognition test (NOLRT), which was effectively restored by pre-treatment with both ketamine or (2R,6R)-HNK. In contrast, in WKYs, which display abnormal stress coping, ketamine, but not (2R,6R)-HNK, had rapid and sustained effects in the forced swim test (FST), a commonly used preclinical screen for antidepressant-like activity. The differential effects of (2R,6R)-HNK observed here reveal a dissociation between drug effects on FST immobility and dHPC synaptic plasticity. Therefore, in the WKY rat model, restoring dHPC LTP was not correlated with ketamine's effects in FST, but importantly, may have contributed to the reversal of hippocampal-dependent cognitive deficits, which are critical features of clinical depression. Our findings support the theory that ketamine may reverse the stress-induced loss of connectivity in key neural circuits by engaging synaptic plasticity processes to "reset the system".
There is growing interest in the therapeutic utility of psychedelic substances, like psilocybin, for disorders characterized by distortions of the self-experience, like depression. Accumulating preclinical evidence emphasizes the role of the glutamate system in the acute action of the drug on brain and behavior; however this has never been tested in humans. Following a double-blind, placebo-controlled, parallel group design, we utilized an ultra-high field multimodal brain imaging approach and demonstrated that psilocybin (0.17 mg/kg) induced region-dependent alterations in glutamate, which predicted distortions in the subjective experience of one’s self (ego dissolution). Whereas higher levels of medial prefrontal cortical glutamate were associated with negatively experienced ego dissolution, lower levels in hippocampal glutamate were associated with positively experienced ego dissolution. Such findings provide further insights into the underlying neurobiological mechanisms of the psychedelic, as well as the baseline, state. Importantly, they may also provide a neurochemical basis for therapeutic effects as witnessed in ongoing clinical trials.
Depression is a major public health problem that affects approximately 4.4% of the global population. Since conventional pharmacotherapies and psychotherapies are only partially effective, as demonstrated by the number of patients failing to achieve remission, alternative treatments are needed. Mindfulness meditation (MM) and psilocybin represent two promising novel treatments that might even have complementary therapeutic effects when combined. Since the current literature is limited to theoretical and empirical underpinnings of either treatment alone, the present review aimed to identify possible complementary effects that may be relevant to the treatment of depression. To that end, the individual effects of MM and psilocybin, and their underlying working mechanisms, were compared on a non-exhaustive selection of six prominent psychological and biological processes that are well known to show impairments in patients suffering from major depression disorder, that is mood, executive functioning, social skills, neuroplasticity, core neural networks, and neuroendocrine and neuroimmunological levels. Based on predefined search strings used in two online databases (PubMed and Google Scholar) 1129 articles were identified. After screening title and abstract for relevance related to the question, 82 articles were retained and 11 were added after reference list search, resulting in 93 articles included in the review. Findings show that MM and psilocybin exert similar effects on mood, social skills, and neuroplasticity; different effects were found on executive functioning, neural core networks, and neuroendocrine and neuroimmune system markers. Potential mechanisms of MM’s effects are enhanced affective self-regulation through mental strategies, optimization of stress reactivity, and structural and functional adjustments of prefrontal and limbic areas; psilocybin’s effects might be established via attenuation of cognitive associations through deep personal insights, cognitive disinhibition, and global neural network disintegration. It is suggested that, when used in combination, MM and psilocybin could exert complementary effects by potentiating or prolonging mutual positive effects, for example, MM potentially facilitating psilocybin-induced peak experiences. Future placebo-controlled double-blind randomized trials focusing on psilocybin-assisted mindfulness-based therapy will provide knowledge about whether the proposed combination of therapies maximizes their efficacy in the treatment of depression or depressive symptomatology.
Psilocybin shows efficacy to alleviate depression in human clinical trials for six or more months after only one or two treatments. Another hallucinogenic drug, esketamine, has recently been U.S. Food and Drug Administration (FDA)-approved as a rapid-acting antidepressant. The mechanistic basis for the antidepressant effects of psilocybin and ketamine appear to be conserved. The efficacy of these two medications has not, however, been directly compared either clinically or preclinically. Further, whether or not a profound subjective existential experience is necessary for psilocybin to have antidepressant effects is unknown. To address these questions, we tested psilocybin, lysergic acid diethylamide (LSD), and ketamine in a rat model for depression. As in humans, a single administration of psilocybin or LSD produced persistent antidepressant-like effects in our model. In contrast, ketamine produced only a transient antidepressant-like effect. Our results indicate that classic psychedelics may have therapeutic efficacy that is more persistent than that of ketamine, and also suggest that a subjective existential experience may not be necessary for therapeutic effects.
Twenty-four hours after administration, ketamine exerts rapid and robust antidepressant effects that are thought to be mediated by activation of the mechanistic target of rapamycin complex 1 (mTORC1). To test this hypothesis, depressed patients were pretreated with rapamycin, an mTORC1 inhibitor, prior to receiving ketamine. Twenty patients suffering a major depressive episode were randomized to pretreatment with oral rapamycin (6 mg) or placebo 2 h prior to the intravenous administration of ketamine 0.5 mg/kg in a double-blind cross-over design with treatment days separated by at least 2 weeks. Depression severity was assessed using Montgomery-Åsberg Depression Rating Scale (MADRS). Rapamycin pretreatment did not alter the antidepressant of ketamine at the 24-h timepoint. Over the subsequent 2-weeks, we found a significant treatment by time interaction (F(8,245) = 2.02, p = 0.04), suggesting a prolongation of the antidepressant effects ketamine by rapamycin. Two weeks following ketamine administration, we found higher response (41%) and remission rates (29%) following rapamycin + ketamine compared to placebo + ketamine (13%, p = 0.04, and 7%, p = 0.003, respectively). In summary, single dose rapamycin pretreatment failed to block the antidepressant effects of ketamine, but it prolonged ketamine's antidepressant effects. This observation raises questions about the role of systemic vs. local blockade of mTORC1 in the antidepressant effects of ketamine, provides preliminary evidence that rapamycin may extend the benefits of ketamine, and thereby potentially sheds light on mechanisms that contribute to depression relapse after ketamine administration.
Chronic stress and depressive-like behaviors in basic neuroscience research have been associated with impairments of neuroplasticity, such as neuronal atrophy and synaptic loss in the medial prefrontal cortex (mPFC) and hippocampus. The current review presents a novel integrative model of neuroplasticity as a multi-domain neurobiological, cognitive, and psychological construct relevant in depression and other related disorders of negative affect (e.g., anxiety). We delineate a working conceptual model in which synaptic plasticity deficits described in animal models are integrated and conceptually linked with human patient findings from cognitive science and clinical psychology. We review relevant reports including neuroimaging findings (e.g., decreased functional connectivity in prefrontal-limbic circuits), cognitive deficits (e.g., executive function and memory impairments), affective information processing patterns (e.g., rigid, negative biases in attention, memory, interpretations, and self-associations), and patient-reported symptoms (perseverative, inflexible thought patterns; inflexible and maladaptive behaviors). Finally, we incorporate discussion of integrative research methods capable of building additional direct empirical support, including using rapid-acting treatments (e.g., ketamine) as a means to test this integrative model by attempting to simultaneously reverse these deficits across levels of analysis.
A single sub-anesthetic dose of ketamine, an NMDA receptor (NMDAR) antagonist, produces rapid and sustained antidepressant actions in depressed patients, addressing a major unmet need for the treatment of mood disorders. Ketamine produces a rapid increase in extracellular glutamate and synaptic formation in the prefrontal cortex, but the initial cellular trigger that initiates these and its behavioral actions has not been identified. To address this question, we used a combination of viral shRNA and conditional mutation to produce cell specific knockdown or deletion of a key NMDAR subunit, GluN2B, implicated in the actions of ketamine. The results demonstrate that the antidepressant actions of ketamine were blocked by GluN2B-NMDAR knockdown on GABA (Gad1) interneurons, as well as subtypes expressing somatostatin (Sst), or parvalbumin (Pvalb), but not glutamate principle neurons in the mPFC. Further analysis of GABA subtypes showed that cell specific knockdown or deletion of GluN2B in Sst interneurons blocked or occluded the antidepressant actions of ketamine and revealed sex-specific differences that are associated with excitatory postsynaptic currents on mPFC principle neurons. These findings demonstrate that GluN2B-NMDARs on GABA interneurons are the initial cellular trigger for the rapid antidepressant actions of ketamine and show sex-specific adaptive mechanisms to GluN2B modulation.
Currently, ketamine is the only legal psychedelic medicine available to mental health providers for the treatment of emotional suffering. Over the past several years, ketamine has come into psychiatric use as an intervention for treatment resistant depression (TRD), administered intravenously without a psychotherapeutic component. In these settings, ketamine’s psychedelic effects are viewed as undesirable “side effects.” In contrast, we believe ketamine can benefit patients with a wide variety of diagnoses when administered with psychotherapy and using its psychedelic properties without need for intravenous (IV) access. Its proven safety over decades of use makes it ideal for office and supervised at-home use. The unique experience that ketamine facilitates with its biological, experiential, and psychological impacts has been tailored to optimize office-based treatment evolving into a method that we call Ketamine Assisted Psychotherapy (KAP). This article is the first to explore KAP within an analytical framework examining three distinct practices that use similar methods. Here, we present demographic and outcome data from 235 patients. Our findings suggest that KAP is an effective method for decreasing depression and anxiety in a private practice setting, especially for older patients and those with severe symptom burden.
Drugs capable of ameliorating symptoms of depression and anxiety while also improving cognitive function and sociability are highly desirable. Anecdotal reports have suggested that serotonergic psychedelics administered in low doses on a chronic, intermittent schedule, so-called "microdosing", might produce beneficial effects on mood, anxiety, cognition, and social interaction. Here, we test this hypothesis by subjecting male and female Sprague Dawley rats to behavioral testing following the chronic, intermittent administration of low doses of the psychedelic N, N-dimethyltryptamine (DMT). The behavioral and cellular effects of this dosing regimen were distinct from those induced following a single high dose of the drug. We found that chronic, intermittent, low doses of DMT produced an antidepressant-like phenotype and enhanced fear extinction learning without impacting working memory or social interaction. Additionally, male rats treated with DMT on this schedule gained a significant amount of body weight during the course of the study. Taken together, our results suggest that psychedelic microdosing may alleviate symptoms of mood and anxiety disorders, though the potential hazards of this practice warrant further investigation.
The main psychedelic component of magic mushrooms is psilocybin, which shows promise as a treatment for depression and other mental disorders. Psychedelic effects are believed to emerge through stimulation of serotonin 2A receptors (5-HT2ARs) by psilocybin’s active metabolite, psilocin. We here report for the first time the relationship between intensity of psychedelic effects, cerebral 5-HT2AR occupancy and plasma levels of psilocin in humans. Eight healthy volunteers underwent positron emission tomography (PET) scans with the 5-HT2AR agonist radioligand [11C]Cimbi-36: one at baseline and one or two additional scans on the same day after a single oral intake of psilocybin (3–30 mg). 5-HT2AR occupancy was calculated as the percent change in cerebral 5-HT2AR binding relative to baseline. Subjective psychedelic intensity and plasma psilocin levels were measured during the scans. Relations between subjective intensity, 5-HT2AR occupancy, and plasma psilocin levels were modeled using non-linear regression. Psilocybin intake resulted in dose-related 5-HT2AR occupancies up to 72%; plasma psilocin levels and 5-HT2AR occupancy conformed to a single-site binding model. Subjective intensity was correlated with both 5-HT2AR occupancy and psilocin levels as well as questionnaire scores. We report for the first time that intake of psilocybin leads to significant 5-HT2AR occupancy in the human brain, and that both psilocin plasma levels and 5-HT2AR occupancy are closely associated with subjective intensity ratings, strongly supporting that stimulation of 5-HT2AR is a key determinant for the psychedelic experience. Important for clinical studies, psilocin time-concentration curves varied but psilocin levels were closely associated with psychedelic experience.
Neural plasticity—the ability to change and adapt in response to stimuli—is an essential aspect of healthy brain function and, in principle, can be harnessed to promote recovery from a wide variety of brain disorders. Many neuropsychiatric diseases including mood, anxiety, and substance use disorders arise from an inability to weaken and/or strengthen pathologic and beneficial circuits, respectively, ultimately leading to maladaptive behavioral responses. Thus, compounds capable of facilitating the structural and functional reorganization of neural circuits to produce positive behavioral effects have broad therapeutic potential. Several known drugs and experimental therapeutics have been shown to promote plasticity, but most rely on indirect mechanisms and are slow-acting. Here, I describe psychoplastogens—a relatively new class of fast-acting therapeutics, capable of rapidly promoting structural and functional neural plasticity. Psychoplastogenic compounds include psychedelics, ketamine, and several other recently discovered fast-acting antidepressants. Their use in psychiatry represents a paradigm shift in our approach to treating brain disorders as we focus less on rectifying “chemical imbalances” and place more emphasis on achieving selective modulation of neural circuits.
Objective:
In addition to N-methyl-d-aspartate receptor antagonism, ketamine produces opioid system activation. The objective of this study was to determine whether opioid receptor antagonism prior to administration of intravenous ketamine attenuates its acute antidepressant or dissociative effects.
Method:
In a proposed double-blind crossover study of 30 adults with treatment-resistant depression, the authors performed a planned interim analysis after studying 14 participants, 12 of whom completed both conditions in randomized order: placebo or 50 mg of naltrexone preceding intravenous infusion of 0.5 mg/kg of ketamine. Response was defined as a reduction ≥50% in score on the 17-item Hamilton Depression Rating Scale (HAM-D) score on postinfusion day 1.
Results:
In the interim analysis, seven of 12 adults with treatment-resistant depression met the response criterion during the ketamine plus placebo condition. Reductions in 6-item and 17-item HAM-D scores among participants in the ketamine plus naltrexone condition were significantly lower than those of participants in the ketamine plus placebo condition on postinfusion days 1 and 3. Secondary analysis of all participants who completed the placebo and naltrexone conditions, regardless of the robustness of response to ketamine, showed similar results. There were no differences in ketamine-induced dissociation between conditions. Because naltrexone dramatically blocked the antidepressant but not the dissociative effects of ketamine, the trial was halted at the interim analysis.
Conclusions:
The findings suggest that ketamine's acute antidepressant effect requires opioid system activation. The dissociative effects of ketamine are not mediated by the opioid system, and they do not appear sufficient without the opioid effect to produce the acute antidepressant effects of ketamine in adults with treatment-resistant depression.
Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders.
The objective of this study is to evaluate cognition in patients using either ketamine or esketamine to treat TRD. We also evaluate if both ketamine and esketamine as one group influence cognition in patients with TRD. Fifty-four patients with TRD were infused with either ketamine or esketamine and were assessed at three time points: baseline, 24h, and 7 days after infusion. We applied neuropsychological tests to evaluate executive functions, processing speed, short term memory, and auditory-verbal episodic memory. There is no cognitive difference between ketamine and esketamine, with the exception of one variable. When considered as one group, ketamine and esketamine do not impair cognition; on the contrary, they improve some neuropsychological functions such as visuospatial short-term memory, executive functions, processing speed, and several measures related to episodic verbal memory. Ketamine and esketamine do not present differing cognitive effects when used in antidepressant doses to treat TRD. Furthermore, they rapidly improve many cognitive aspects of patients with TRD at 24h after the infusion and maintain these effects for at least 7 days.
Significance
Ketamine exerts rapid antidepressant action in some patients with treatment-resistant depression. This study demonstrates that Reelin, its receptor apolipoprotein E receptor 2 (Apoer2), and downstream signaling via Src family kinases are required for ketamine-mediated behavioral changes and associated synaptic plasticity in the CA1 hippocampal region. Our findings suggest that a permissive role of Reelin-dependent synaptic signaling in regulating the basal activity of N-methyl-D-aspartate receptors may be essential for ketamine’s antidepressant efficacy.
Currently available antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), generally require weeks to months to produce a therapeutic response, but the mechanism of action underlying the delayed onset of antidepressant-like action remains to be elucidated. The balance between excitatory glutamatergic pyramidal neurons and inhibitory γ-aminobutyric acid (GABA) interneurons, i.e., the excitation:inhibition functional (E:I) balance, in the medial prefrontal cortex (mPFC) is critical in regulating several behaviors and might play an important mediating role in the mechanism of rapid antidepressant-like action reported by several studies. In the present study, the multichannel electrophysiological technique was used to record the firing activities of pyramidal neurons and interneurons and investigate the effects of a single dose of fluoxetine and ketamine (both 10 mg/kg, i.p.) on the E:I functional balance in the rat mPFC after 90 min or 24 h, and the forced swimming test (FST) was used to evaluate the antidepressant-like effects of fluoxetine and ketamine. The present study also explored the effects of chronic treatment with fluoxetine (10 mg/kg, i.g.) for 7 d or 21 d on the E:I functional balance in the mPFC. The present results suggested that a single dose of ketamine could both significantly increase the firing activities of pyramidal neurons and significantly decrease the firing activities of interneurons in the mPFC and exerted significant antidepressant-like action on the FST after 90 min and 24 h, but fluoxetine had no such effects under the same conditions. However, chronic treatment with fluoxetine for 21 d (but not 7 d) could significantly affect the firing activities of pyramidal neurons and interneurons in the mPFC. Taken together, the present results indicated that rapid regulation of the E:I functional balance in the mPFC might be an important common mechanism of rapid-acting antidepressants and the delayed onset of SSRIs might be partly attributed to their inability to rapidly regulate the E:I functional balance in the mPFC. The present study provided a new entry point to the development of rapid-acting antidepressants.
Significance
Psychedelic compounds, such as psilocybin, have beneficial actions in several psychiatric diseases. They also produce strong alterations of consciousness, which may be a barrier to their widespread use. We found that psilocybin has fast-acting antidepressant-like properties in mice. Using multiple assays of hedonic behavior and an antagonist of prohallucinatory 5-HT2A receptors, we further suggest that altered perception may not be necessary for its therapeutic actions. We also showed that psilocybin strengthens connections between brain cells in regions important for processing rewards and emotions. These experiments suggest that it may be possible to retain the beneficial actions of psilocybin while minimizing the alterations in consciousness, thereby accelerating its use in the clinic.
Major depressive disorder (MDD) is among the most prevalent mental health disorders worldwide, and it is associated with a reduced quality of life and enormous costs to health care systems. Available drug treatments show low-to-moderate response in most patients, with almost a third of patients being non-responders (treatment-resistant). Furthermore, most currently available medications need several weeks to achieve therapeutic effects, and the long-term use of these drugs is often associated with significant unwanted side effects and resultant reductions in treatment compliance. Therefore, more effective, safer, and faster-acting antidepressants with enduring effects are needed. Together with ketamine, psychedelics (or classic or serotoninergic hallucinogens) such as lysergic acid diethylamide (LSD), psilocybin, and ayahuasca are among the few compounds with recent human evidence of fast-acting antidepressant effects. Several studies in the 1950s to 1970s reported antidepressive and anxiolytic effects of these drugs, which are being confirmed by modern trials (LSD, one trial; psilocybin, five trials; ayahuasca, two trials). The effects of these drugs appear to be produced primarily by their agonism at serotonin (5-hydroxytryptamine, 5-HT) receptors, especially the 5-HT2A receptor. Considering the overall burden of MDD and the necessity of new therapeutic options, the promising (but currently limited) evidence of safety and efficacy of psychedelics has encouraged the scientific community to explore more fully their beneficial effects in MDD.
Major depressive disorder (MDD) is characterized by heterogeneous cognitive, affective and somatic symptoms. Hence, the investigation of differential treatment effects on these symptoms as well as the identification of symptom specific biomarkers might crucially contribute to the development of individualized treatment strategies.
We here aimed to examine symptom specific responses to treatment with ketamine, which repeatedly demonstrated rapid antidepressant effects in severe MDD. Additionally, we investigated working memory (WM) related brain activity associated with changes in distinct symptoms in order to identify specific response predictors. In a sample of 47 MDD patients receiving a single sub-anesthetic dose of ketamine, we applied a three-factor solution of the Beck Depression Inventory (BDI) to detect symptom specific changes 24 hours post-infusion. A subsample of 16 patients underwent additional fMRI scanning during an emotional working memory task prior to ketamine treatment. Since functional aberrations in the default mode network (DMN) as well as in the dorsolateral prefrontal cortex (DLPFC) have been associated with impaired cognitive and emotional processing in MDD, we investigated neural activity in these regions.
Our results showed that ketamine differentially affects MDD symptoms, with the largest symptom reduction in the cognitive domain. WM related neuroimaging results indicated that a more pronounced effect of ketamine on cognitive symptoms is predicted by lower DMN deactivation and higher DLPFC activation. Findings thereby not only indicate that ketamine’s antidepressant efficacy is driven by a pro-cognitive mechanism, but also suggest that this might be mediated by increased potential for adaptive adjustment in the circumscribed brain regions.
Layer V pyramidal neurons constitute principle output neurons of the medial prefrontal cortex (mPFC)/neocortex to subcortical regions including the intralaminar/midline thalamic nuclei, amygdala, basal ganglia, brainstem nuclei and the spinal cord. The effects of 5-hydroxytryptamine (5-HT) on layer V pyramidal cells primarily reflect a range of excitatory influences through 5-HT2A receptors and inhibitory influences through non-5-HT2A receptors, including 5-HT1A receptors. While the 5-HT2A receptor is primarily a postsynaptic receptor on throughout the apical dendritic field of 5-HT2A receptors, activation of a minority of 5-HT2A receptors also appears to increase spontaneous excitatory postsynaptic currents/potentials (EPSCs/EPSPs) via a presynaptic effect on thalamocortical terminals arising from the midline and intralaminar thalamic nuclei. Activation of 5-HT2A receptors by the phenethylamine hallucinogen also appears to increase asynchronous release of glutamate upon the layer V pyramidal dendritic field, an effect that is suppressed by 5-HT itself through non-5-HT2A receptors. Serotonergic hallucinogens acting on 5-HT2A receptors also appears to increase gene expression of immediate early genes (iEG) and other receptors appearing to induce an iEG-like response like BDNF. Psychedelic hallucinogens acting on 5-HT2A receptors also induce head twitches in rodents that appear related to induction of glutamate release. These electrophysiological, biochemical and behavioral effects of serotonergic hallucinogens appear to be related to modulating glutamatergic thalamocortical neurotransmission and/or shifting the balance toward 5-HT2A receptor activation and away from non-5-HT2A receptor activation. These 5-HT2A receptor induced responses are modulated by feedback homeostatic mechanisms through mGlu2, mGlu4, and mGlu8 presynaptic receptors on thalamocortical terminals. These 5-HT2A receptor and glutamatergic interactions also appear to play a role on higher cortical functions of the mPFC such as motoric impulsivity and antidepressant-like behavioral responses on the differential-reinforcement-of low rate 72-s (DRL 72-s schedule). These mutually opposing effects between 5-HT2A receptor and mGlu autoreceptor activation (e.g., blocking 5-HT2A receptors and enhancing activity at mGlu2 receptors) may play a clinical role with respect to currently prescribed or novel antidepressant drugs. Thus, there is an important balance between 5-HT2A receptor activation and activation of mGlu autoreceptors on prefrontal cortical layer V pyramidal cells with respect to the electrophysiological, biochemical and behavioral effects serotonergic hallucinogenic drugs.
Pilot studies have hinted that serotonergic psychedelics such as psilocybin may relieve depression, and could possibly do so by promoting neural plasticity. Intriguingly, another psychotomimetic compound, ketamine, is a fast-acting antidepressant and induces synapse formation. The similarities in behavioral and neural effects have been puzzling because the compounds target distinct molecular receptors in the brain. In this opinion article, we develop a conceptual framework that suggests the actions of ketamine and serotonergic psychedelics may converge at the dendrites, to both enhance and suppress membrane excitability. We speculate that mismatches in the opposing actions on dendritic excitability may relate to these compounds’ cell-type and region selectivity, their moderate range of effects and toxicity, and their plasticity-promoting capacities.
Background
Psilocybin is a serotonergic psychedelic found in “magic mushrooms” with a putative therapeutic potential for treatment-resistant depression, anxiety, obsessive-compulsive disorder, and addiction. In rodents, psilocybin acutely induces plasticity-related immediate early genes in cortical tissue; however, studies into the effects on subcortical regions, of different doses, and the subsequent translation of corresponding proteins are lacking.
Methods
We examined the acute effects of a single administration of psilocybin (0.5–20 mg/kg) on the expression of selected genes in the prefrontal cortex and hippocampus. In total, 46 target genes and eight reference genes were assessed using real-time quantitative polymerase chain reaction. Corresponding protein levels of the three most commonly regulated genes were assessed using Western blotting.
Results
In the prefrontal cortex, psilocybin increased the expression of Cebpb, c-Fos, Dups1, Fosb, Junb, Iκβ-α, Nr4a1, P11, Psd95, and Sgk1, and decreased the expression of Clk1. In the hippocampus, psilocybin strongly increased the expression of Arrdc2, Dusp1, Iκβ-α, and Sgk1 in a dose-dependent manner, and decreased the expression of Arc, Clk1, Egr2, and Ptgs2. Protein levels of Sgk1, Dusp1, and Iκβ-α showed only partial agreement with transcriptional patterns, stressing the importance of assessing downstream translation when investigating rapid gene responses.
Conclusion
The present study demonstrates that psilocybin rapidly induces gene expression related to neuroplasticity, biased towards the prefrontal cortex, compared to the hippocampus. Our findings provide further evidence for the rapid plasticity-promoting effects of psilocybin.
Cortical neuron atrophy is a hallmark of depression and includes neurite retraction, dendritic spine loss, and decreased synaptic density. Psychoplastogens, small molecules capable of rapidly promoting cortical neuron growth, have been hypothesized to produce long-lasting positive effects on behavior by rectifying these deleterious structural and functional changes. Here we demonstrate that ketamine and LSD, psychoplastogens from two structurally distinct chemical classes, promote sustained growth of cortical neurons after only short periods of stimulation. Furthermore, we show that psychoplastogen-induced cortical neuron growth can be divided into two distinct epochs: an initial stimulation phase requiring TrkB activation and a growth period involving sustained mTOR and AMPA receptor activation. Our results provide important temporal details concerning the molecular mechanisms by which next-generation antidepressants produce persistent changes in cortical neuron structure, and they suggest that rapidly excreted psychoplastogens might still be effective neurotherapeutics with unique advantages over compounds like ketamine and LSD.
Objective
To conduct a systematic review of modern‐era (post‐millennium) clinical studies assessing the therapeutic effects of serotonergic psychedelics drugs for mental health conditions. Although the main focus was on efficacy and safety, study characteristics, duration of antidepressants effects across studies, and the role of the subjective drug experiences were also reviewed and presented.
Method
A systematic literature search (1st Jan 2000 to 1st May 2020) was conducted in Pubmed and Psychinfo for studies of patients undergoing treatment with a serotonergic psychedelic.
Results
Data from 16 papers, representing 10 independent psychedelic‐assisted therapy trials (psilocybin=7, ayahuasca = 2, LSD=1) were extracted, presented in figures and tables, and narratively synthesized and discussed. Across these studies, a total of 188 patients suffering either anxiety and/or depressive symptoms associated with cancer (C‐RPD), major depressive disorder (MDD), obsessive compulsive disorder (OCD) or substance use disorder (SUD) were included. The reviewed studies established feasibility and evidence of safety, alongside promising early data of efficacy in the treatment of depression, anxiety, OCD, and tobacco and alcohol use disorders. For a majority of patients, the therapeutic effects appeared to be long‐lasting (weeks‐months) after only 1 to 3 treatment session(s). All studies were conducted in line with guidelines for the safe conduct of psychedelic therapy and no severe adverse events were reported.
Conclusion
The resurrection of clinical psychedelic research provides early evidence for treatment efficacy and safety for a range of psychiatric conditions, and constitutes an exciting new treatment avenue in a health area with major unmet needs.
Hallucinogens like lysergic acid diethylamide (LSD), psilocybin, and substituted N-benzyl phenylalkylamines are widely used recreationally with psilocybin being considered as a therapeutic for many neuropsychiatric disorders including depression, anxiety, and substance abuse. How psychedelics mediate their actions-both therapeutic and hallucinogenic-are not understood, although activation of the 5-HT2A serotonin receptor (HTR2A) is key. To gain molecular insights into psychedelic actions, we determined the active-state structure of HTR2A bound to 25-CN-NBOH-a prototypical hallucinogen-in complex with an engineered Gαq heterotrimer by cryoelectron microscopy (cryo-EM). We also obtained the X-ray crystal structures of HTR2A complexed with the arrestin-biased ligand LSD or the inverse agonist methiothepin. Comparisons of these structures reveal determinants responsible for HTR2A-Gαq protein interactions as well as the conformational rearrangements involved in active-state transitions. Given the potential therapeutic actions of hallucinogens, these findings could accelerate the discovery of more selective drugs for the treatment of a variety of neuropsychiatric disorders.
Despite preclinical evidence for psychedelic-induced neuroplasticity, confirmation in humans is grossly lacking. Given the increased interest in using low doses of psychedelics for psychiatric indications, and the importance of neuroplasticity in the therapeutic response, this placebo-controlled within-subject study investigated the effect of single low LSD doses (5, 10, and 20 mcg) on circulating BDNF levels, in healthy volunteers. Blood samples were collected every two hours over six hours, and BDNF levels were determined afterward in blood plasma using ELISA. The findings demonstrated an increase in BDNF blood plasma levels at 4 hours (5 mcg) and 6 hours (5 and 20 mcg) compared to the placebo. The finding that LSD acutely increases BDNF levels warrants studies in patient populations.
Serotoninergic hallucinogens include drugs such as lysergic acid diethylamide (LSD), dimethyltryptamine (DMT) and psilocybin. Recent trials with single/few doses of these compounds show that they induce rapid and sustained antidepressive, anxiolytic, and antiaddictive effects. These effects are also observed in religious groups using the DMT-containing brew ayahuasca. The agonist action of these substances on 5-HT2A receptors expressed in frontal and limbic areas increase glutamatergic transmission and neuroplasticity. These neurochemical effects are associated with acute alterations on self-perception and increases in introspection and positive mood, and with subacute and long-term decreases in psychiatric symptoms, increases in some personality traits such as openness, improvements in emotional processing, and increases in empathy. These are preliminary but promising results that should be further explored in controlled trials with larger sample sizes, especially considering that these compounds could be beneficial in the treatment of treatment-resistant psychiatric disorders.
Objectives: Synaptic plasticity and brain-derived neurotrophic factor (BDNF) signalling are proposed to play key roles in antidepressant drug action. Ketamine, an N-methyl-D-aspartate receptor antagonist and putative antidepressant, may increase synaptic plasticity in prefrontal cortex through higher expression of BDNF. Furthermore, ketamine was shown to change resting-state functional connectivity (RSFC) of dorsomedial prefrontal cortex (dmPFC).
Methods: In a randomised, placebo-controlled study, we investigated acutely (100 min) and at 24 h following subanesthetic ketamine infusion which dmPFC seeded RSFC changes are most strongly associated with plasma BDNF level changes in 53 healthy participants (21 females, age: 24.4 ± 2.9 years) using 7 T-fMRI.
Results: We observed higher relative levels of BDNF 2 h and 24 h after ketamine compared to placebo. Whole-brain regression revealed that the change in BDNF after 24 h was associated with RSFC decreases from dmPFC to posterior cingulate cortex and ventromedial PFC at 24 h and exploratively also at the 100 min measurement point. Follow-up analyses revealed that RSFC reductions following ketamine were restricted to subjects showing increased BDNF levels at 24 h.
Conclusions: Our findings indicate BDNF level dynamics following ketamine are related to acute and 24 h RSFC changes. Particularly when BDNF increases are observed after ketamine infusion, a disconnection from dmPFC after 24 h is seen and may reflect synaptic plasticity effects.
Why is ketamine an antidepressant?
A better understanding of the mechanisms underlying the action of antidepressants is urgently needed. Moda-Sava et al. explored a possible mode of action for the drug ketamine, which has recently been shown to help patients recover from depression (see the Perspective by Beyeler). Ketamine rescued behavior in mice that was associated with depression-like phenotypes by selectively reversing stress-induced spine loss and restoring coordinated multicellular ensemble activity in prefrontal microcircuits. The initial induction of ketamine's antidepressant effect on mouse behavior occurred independently of effects on spine formation. Instead, synaptogenesis in the prefrontal region played a critical role in nourishing these effects over time. Interventions aimed at enhancing the survival of restored synapses may thus be useful for sustaining the behavioral effects of fast-acting antidepressants.
Science , this issue p. eaat8078 ; see also p. 129
Significance
Despite available medications for depression, currently approved antidepressants take months to exert therapeutic effects, and ∼30% of patients remain treatment resistant. In contrast, a single subanesthetic dose of ketamine exerts rapid (within hours) and sustained antidepressant actions. Preclinical studies indicate that the ketamine metabolite ( 2R , 6R )-hydroxynorketamine [( 2R , 6R )-HNK] is a rapid-acting antidepressant candidate with limited adverse effects compared with ketamine. Using behavioral, genetic, and pharmacological approaches and EEG measurements, we determined that the mechanism underlying antidepressant-relevant actions of ( 2R , 6R )-HNK converges with metabotropic glutamate receptor subtype 2 (mGlu 2 ) receptor signaling and identified high-frequency EEG oscillations as a marker associated with rapid antidepressant responses. Our data support the use of individually subtherapeutic doses of mGlu 2 receptor inhibitors with ketamine or ( 2R , 6R )-HNK in clinical trials for the treatment of depression.
Depression and anxiety are psychiatric diagnoses commonly associated with low quality of life and low percentage of responsiveness by patients treated with currently available drugs. Thus, research into alternative compounds to treat these disorders is essential to guarantee a patient's remission. The last decade has witnessed a revamped interest for the application of psychedelic medicine for the treatment of mental disorders due to anecdotal reports and clinical studies which show that low doses of D-lysergic acid diethylamide (LSD) and psilocybin may have antidepressant effects. LSD and psilocybin have demonstrated mood-modulating properties likely due to their capacity to modulate serotonergic (5-HT), dopaminergic (DA) and glutamatergic systems. LSD, belonging to the category of “classic halluginogens,” interacts with the 5-HT system through 5HT1A, and 5HT2A receptors, with the DA system through D2 receptors, and indirectly also the glutamatergic neurotransmission thought the recruitment of N-methyl-D-aspartate (NMDA) receptors. Randomized clinical studies have confirmed its antidepressant and anxiolytic effects in humans. Thus, in this chapter, we will review the pharmacology of psychedelic drugs, report the most striking clinical evidence which substantiate the therapeutic potentials of these fascinating compounds in mood disorders, and look into the horizon of where psychedelic medicine is heading.
Aims and methods:
Here, we investigate the effects of N,N-dimethyltryptamine (DMT), the principle hallucinogenic component of ayahuasca, in rodent behavioral assays relevant to anxiety and depression using adult, male, Sprague-Dawley rats.
Results:
We find that while DMT elicits initial anxiogenic responses in several of these paradigms, its long-lasting effects tend to reduce anxiety by facilitating the extinction of cued fear memory. Furthermore, DMT reduces immobility in the forced swim test, which is a characteristic behavioral response induced by many antidepressants.
Conclusions:
Our results demonstrate that DMT produces antidepressant and anxiolytic behavioral effects in rodents, warranting further investigation of ayahuasca and classical psychedelics as treatments for depression and post-traumatic stress disorder.
In the past three decades, our understanding of brain-behavior relationships has been significantly shaped by research using non-invasive brain stimulation (NIBS) techniques. These methods allow non-invasive and safe modulation of neural processes in the healthy brain, enabling researchers to directly study how experimentally altered neural activity causally affects behavior. This unique property of NIBS methods has, on the one hand, led to groundbreaking findings on the brain basis of various aspects of behavior and has raised interest in possible clinical and practical applications of these methods. On the other hand, it has also triggered increasingly critical debates about the properties and possible limitations of these methods. In this review, we discuss these issues, clarify the challenges associated with the use of currently available NIBS techniques for basic research and practical applications, and provide recommendations for studies using NIBS techniques to establish brain-behavior relationships.